15 
Malaria Chemoprophylaxis
Patricia Schlagenhauf, Mary Elizabeth Wilson, Eskild Petersen,
KEY POINTS
• All travelers to malaria-endemic areas need to:
• Be aware of the risk of malaria at the destination and
understand that it is a serious, potentially fatal, infection.
• Know how to best prevent malaria with personal protection
measures against mosquito bites and chemoprophylaxis
(where appropriate).
• Seek medical attention urgently should they develop fever during
travel and “think malaria” after returning from endemic areas.
• The use of chemoprophylaxis drug regimens should be carefully
directed at high-risk travelers where their benefit outweighs the
risk of severe adverse events.
APPROACH TO MALARIA PREVENTION
Protection against malaria can be summarized into four principles: (1)
assessing individual risk, (2) preventing mosquito bites with personal
protection measures (PPMs), (3) taking the “THINK MALARIA”
approach if fever develops during or after travel, and (4) using malaria
chemoprophylaxis.
Assessing Individual Risk—Parasite, Place, and Person
Malaria remains the top specific cause of fever in returning travelers.1
Estimating a traveler’s risk in the pretravel setting is based on a detailed
travel itinerary, parasite epidemiology, and specific risk behaviors of
the traveler. The risk of acquiring malaria will vary according to the
geographic area visited (e.g., Africa versus Southeast Asia), the travel
destination within different geographic areas (urban versus rural), type
of accommodation (camping versus well-screened or air-conditioned
building), duration of stay (1-week business travel versus 3-month
overland trek), time of travel (high or low malaria transmission season;
risk usually is highest during and immediately after the rainy season),
efficacy of and adherence to preventive measures used (e.g., treated
bednets, chemoprophylaxis), and elevation of destination (malaria
transmission is rare above 2000 m).2–9
Constantly updated information on malaria epidemiology is available
online from several sources, including the Centers for Disease Control
and Prevention (CDC), the World Health Organization (WHO),
NaTHNac, SafeTravel, and Health Canada.10–13
The travel medicine advisor must consider several types of informa-
tion in deciding whether to recommend chemoprophylaxis. The traveler’s
preferences should also inform the decision. A framework should take
into account the parasite, place, and person. A key focus in preparing
the traveler should be on reducing the risk of acquiring malaria and
preventing severe illness and death from malaria during or after travel.
Anne McCarthy, and Lin H. Chen
• Intending users of chemoprophylaxis need to be screened for
contraindications and counseled regarding possible adverse events
and drug interactions.
• Making recommendations about chemoprophylaxis is a complex
process that requires integrating many kinds of data. The decision
process must be responsive to the dynamic epidemiology of
malaria, availability of new drugs, new data about existing drugs
and their prices, results from new studies, and changes in
resistance patterns. Access to current guidelines is essential.
This needs to be weighed against the risk of intercurrent adverse events
including serious adverse events resulting from taking a chemoprophy-
lactic drug. Thus the risk assessment is a balancing act and the clinician
needs sufficient information about the potential risk of malaria to be
able to balance it against the potential adverse events associated with
chemoprophylaxis. Each piece of information that suggests lower or
higher risk aids in developing a composite of risk—albeit a general
estimate of risk. Any traveler who will visit an area with any risk of
malaria should know about steps to take in the event illness, which
may be malaria, develops after travel so that they can actively seek
informed care. This should be part of the consultation whether or not
chemoprophylaxis is prescribed. Detailed information about insect
avoidance should also be included, regardless if a chemoprophylaxis is
prescribed. The latter will help to protect against multiple infections,
in addition to malaria.
In the risk assessment consider the following key questions:
1. Is malaria present in the destination? Is falciparum malaria present?
2. What is the intensity of transmission in the areas that the traveler
will visit? Destinations with high intensity of transmission of
Plasmodium falciparum would generate a strong recommendation
for chemoprophylaxis.
3. What are the drug susceptibility patterns of the parasites in that
geographic region? Which antimalarials are effective in that
region?
4. Will the traveler visit friends and relatives (VFR) in sub-Saharan
Africa? Several studies have shown that African VFRs1–4 have a high
risk of malaria, are unlikely to seek pretravel advice, and many are
unaware that their preexisting semiimmunity to malaria wanes over
time and is no longer protective.
5. What kind of accommodation will the traveler have? Will there be
air conditioning? Bednets? What medical resources are available
locally?
145
 CHAPTER 15  Malaria Chemoprophylaxis 145.e1

Abstract Keywords
Malaria chemoprophylaxis is probably the most complex area of pretravel Atovaquone/proguanil
advice. The travel medicine advisor must have in-depth knowledge of Chemoprophylaxis
all available chemoprophylactic drugs as well as detailed knowledge of Chloroquine
the current epidemiology of malaria at travelers’ destinations. The current Doxycycline
priority antimalarials are atovaquone/proguanil, doxycycline, and Malaria
mefloquine. Prescribing of mefloquine is constrained by new Federal Mefloquine
Drug Administration (FDA), European Medicines Agency (EMA), and Primaquine
national recommendations. Chloroquine is rarely used as a priority Tafenoquine
prophylaxis due to widespread resistance. Primaquine is an alternative Traveler
for some travelers and is included in US and Canadian guidelines.
Tafenoquine may be an option in the near future. Due to a risk of
hemolysis, glucose-6-phosphate dehydrogenase (G6PD) testing is required
prior to using primaquine or tafenoquine. The choice of drug will be
influenced by tolerability, efficacy, adherence, and cost considerations
and must also take into account traveler comorbidities and comedications.
The ideal prophylactic agent is effective, safe, cheap, and has activity
against liver stage and blood stage parasites.
146 SECTION 4 Malaria
6. What is the duration of travel? Longer duration of travel confers
higher risk.5,6
7. Are there relevant personal factors that affect likelihood of expo-
sure and severity of infection. Will the traveler use repellents and
other PPMs? Is the traveler likely to be adherent to PPMs and
chemoprophylaxis?
8. Is the traveler pregnant or planning to become pregnant? This could
affect the severity of infection and would influence choice of drug.
Is the traveler breastfeeding?
9. Does the traveler have contraindications or preexisting conditions
such as renal or hepatic disease that could affect excretion or
metabolism of certain drugs? Does the traveler have allergies or
medical problems that would affect drug choice? Is the traveler taking
other medication with potential for drug-drug interactions?7
More difficult decisions ensue when travelers are going to areas with
low levels of malaria transmission, seasonal transmission, or predomi-
nantly or all nonfalciparum malaria. Traveler preferences can play a
key role in deciding whether to use chemoprophylaxis in areas where
risk of malaria is low. Standby emergency self-treatment for presumptive
malaria is an option in some instances.
The travel medicine advisor must have in-depth knowledge of the
likely profile and contraindications of all available chemoprophylactic
drugs as well as an in-depth knowledge of the current epidemiology
of malaria.
The choice of a specific agent is often easier than the decision whether
to recommend chemoprophylaxis. In the event that drug choices are
constrained because of allergies, comorbidities, or neuropsychiatric
history, a different threshold may be used if one is faced with using a
drug with more side effects.
Some travelers strongly prefer to avoid drugs and may not adhere
to a drug regimen, if prescribed. Some travelers prefer drugs administered
once weekly, others prefer daily doses. For travelers visiting high-risk
destinations who refuse chemoprophylaxis, clinicians have an obligation
to provide clear recommendations and descriptions of consequences
of malaria. Economic factors play a decisive role for some travelers,
and providers should be aware the travelers may be unable to afford
certain drugs and should factor that into the decision-making process.
In addition to being safe, effective, easy to use, and inexpensive, the
ideal prophylactic agent would have activity against liver stage and
blood stage parasites.8
Preventing Mosquito Bites With Personal
Protection Measures
All travelers to malaria-endemic areas need to be instructed how best
to avoid bites from Anopheles mosquitoes, which transmit malaria. Any
measure that reduces exposure to the dusk-to-dawn female Anopheles
mosquito will reduce the risk of acquiring malaria. The travel health
advisor should spend time explaining the use of PPMs against mosquito
bites, encouraging adherence with these measures, and advising the
use of a combination of several antimosquito methods such as air-
conditioning, bednets, impregnated clothes, and repellents. Studies have
demonstrated that N,N-diethyl-3-methylbenzamide (DEET)–based
repellents provide adequate protection against mosquito bites, and
preparations containing approximately 20% DEET can be recommended
for adults and children.9–12 A randomized placebo-controlled trial
examined the use of DEET-based repellents (20% DEET) during the
second and third trimesters of pregnancy. No adverse events were
identified in mother or fetus, providing reassurance regarding the use
of DEET-based repellents by pregnant women.13 Another widely used
repellent is icaridin (KBR 3023, Bayrepel [RS]-sec-butyl2-[2-hydroxyethyl]
piperidine-1-carboxylate). This repellent appears to be less irritating
than DEET products and has good cosmetic properties. One controlled
field study showed that 19% icaridin was effective and offered a protection
equivalent to that of a long-acting DEET formulation.14 A recent sys-
tematic review found that DEET, icaridin, ethyl-butylacetyl-amino-
propionate (EBAAP), and citriodora are all effective against Anopheles
spp., providing, on average, 4–10 hours of protection.15 Insecticide-
impregnated bednets (permethrin or similarly treated) are safe for
children and pregnant women and are an effective prevention strategy
that is often underused by travelers.
Taking the “THINK MALARIA” Approach if Fever
Develops During or After Travel
Travelers should be informed that although PPMs and the use of
chemoprophylaxis can markedly reduce the risk of contracting malaria,
these interventions do not guarantee complete protection. Symptoms
of malaria may occur as early as 1 week after the first exposure, and as
late as several years after leaving a malaria zone whether or not chemo
suppression has been used. Approximately 90% of malaria-infected
travelers do not become symptomatic until they return home.16–18 Most
travelers who acquire falciparum malaria will develop symptoms within
3 months of exposure.16–18 Falciparum malaria can be effectively treated
early in its course, but delays in diagnosis and therapy may result in
serious and even fatal outcomes.19
Using Malaria Chemoprophylaxis
The rest of this chapter will focus on malaria chemoprophylaxis. For
most at-risk travelers a choice between atovaquone-proguanil, meflo-
quine, and doxycycline will have to be made. Less often primaquine or
(increasingly rarely) chloroquine (plus proguanil) may be used. Deciding
which agent is best requires an individual assessment of malaria risk
and the specific advantages and disadvantages of each regimen (Tables
15.1–15.5). All chemoprophylactic medications need to be started before
travel—mefloquine (3–4 weeks), doxycycline (1 day), atovaquone-
proguanil (1 day), and primaquine (1 day)—taken regularly during
travel and continued after leaving the malaria-endemic area (a 4-week,
posttravel drug intake is required for all regimens except atovaquone-
proguanil and primaquine, where only 1-week posttravel intake is
required) (Fig. 15.1).
Agents such as atovaquone-proguanil and primaquine are called
causal prophylactics because they act on malaria parasites early in the
lifecycle in the liver, and therefore may be discontinued 1 week after
leaving an endemic area. This advantage makes these agents attractive
for high-risk but short-duration travel (Fig. 15.2).
All antimalarials are potent drugs and are associated with an
appreciable risk of adverse events including visual disorders,20,21 neu-
ropsychiatric disorders,22,23 and gastrointestinal (GI) disorders.23,24 Some
events are distressing enough to lead 1%–7% of travelers to discontinue
their prescribed chemoprophylactic regimen.23,25 Traveler adherence
with posttravel intake has traditionally been poor.
CURRENT CHEMOPROPHYLACTIC
DRUG REGIMENS
This section will review currently recommended chemoprophylactic
drug regimens in detail, including indications, adverse events, drug
resistance, precautions, and contraindications.
Chloroquine, Hydroxychloroquine,
Chloroquine/Proguanil
Description, Pharmacology, and Mode of Action.  Chloroquine
was developed in Germany in the 1930s and although initially considered
“too toxic for human use,” it was further evaluated by the Allied powers
in the 1940s and found to be an outstanding antimalarial drug that has
 CHAPTER 15  Malaria Chemoprophylaxis 147

TABLE 15.1  Malaria Chemoprophylactic TABLE 15.3  Incidence of Severea Events

Regimens for Persons at Risk by Zone a
During Malaria Chemoprophylaxis in
Zone Drug(s) of Choiceb Alternatives
Travelers
No chloroquine Chloroquine Mefloquine, doxycycline, or Study Population MQ C+P DX A+P
resistance atovaquone/proguanil Phillips 1996 Australian 11.2 – 6.5 –
Chloroquine Mefloquine or First choice: primaquinec; Schlagenhauf 1996 Swiss 11.2 – – –
resistance atovaquone/proguanil second choice: chloroquine Barrett 1996 United Kingdom 17 16 – –
or doxycycline plus proguanild Steffen 1993 European 13 16 – –
Chloroquine and Doxycycline or Hoghb 2000 International – 2 – 0.2
mefloquine atovaquone/proguanil Overboschb 2001 International 5 – – 1
resistance Schlagenhauf 2003c International 10.5 12.4 5.9 6.7
Terrell 2015 UK soldiers in Kenya 12.5 _ 22.2 _
Adult Doses
a
Chloroquine 300 mg (base) weekly Interferes with daily activity or impacted performance.
b
phosphate Stopped taking antimalarials.
c
Sought medical attention in context of the study.
Mefloquine 250 mg (salt in United States; base elsewhere) weekly
A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX,
Atovaquone/ One tablet daily (250 mg/100 mg)
doxycycline; MQ, mefloquine.
proguanil
Doxycycline 100 mg daily
Primaquine 30 mg (base) dailyc
Proguanil 200 mg dailye
TABLE 15.4  Incidence of Seriousa Adverse
Events During Malaria Chemoprophylaxis
a
IMPORTANT NOTE: Protection from mosquito bites (insecticide-
treated bednets, DEET-based insect repellents, etc.) is the first line
of defense against malaria for all travelers. In the Americas and Report Population MQ C+P DX A+P
Southeast Asia, chemoprophylaxis is recommended only for travelers MacPherson 1992 68
Canadian 1/20,000 ? ?
who will be exposed outdoors during evening or nighttime in rural
Steffen 19938 European 1/10,000 1/13,600
areas.
b Croft 199670 UK soldiers 1/6000
Chloroquine and mefloquine are to be taken once weekly, beginning
1 week before entering the malarial area, during the stay and for 4 Barrett 199663 UK 1/600 1/1200
weeks after leaving. Doxycycline and proguanil are taken daily, Roche Drug Safety 1997 Worldwide 1/20,000
starting 1 day before entering malarial areas, during the stay, and for a
Hospitalization.
4 weeks after departure. Atovaquone/proguanil and primaquine are
A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX,
taken once daily, starting 1 day before entering the malarial area,
doxycycline; MQ, mefloquine.
during the stay, and may be discontinued 7 days after leaving the
endemic area.
c
Contraindicated in glucose-6-phosphate dehydrogenase (G6PD)
deficiency and during pregnancy. Not presently licensed for this use.
A G6PD level must be performed before prescribing. been in continuous use for over 50 years. Widespread resistance limits
d
Chloroquine plus proguanil is less efficacious than mefloquine, the use of chloroquine and its combinations by travelers. This
doxycycline, or AP in these areas. 4-aminoquinoline drug is chemically a racemate, and both enantiomers
e
Should only be used in combination with chloroquine. have equivalent antimalarial activity. Preparations are available as
phosphate, sulfate, and hydrochloride salts, under a wide variety of
trade names. In the United States, hydroxychloroquine is recommended
as an alternative for chemoprophylaxis in areas with chloroquine-sensitive
P. falciparum. The combination of proguanil 200 mg (usually as
Paludrine) daily and chloroquine base 300 mg weekly has been used
extensively.
TABLE 15.2  Incidence of Any Adverse Chloroquine is a potent blood schizonticide, active against the
Event During Malaria Chemoprophylaxis in erythrocytic forms of sensitive strains of all species of malaria, and is
Nonimmune Travelers also gametocidal against P. vivax, P. malariae, and P. ovale. The site of
Study Population MQ C+P DX A+P action of chloroquine is within the lysosome of the blood stage parasite,26
where it complexes with hemin and prevents its conversion to the
Steffen 19938 Travelers 24 35 – – nontoxic hemozoin.26 Proguanil is converted to the active cycloguanil,
Boudreau 199382 US Marines 43 46 – – which is a dihydrofolate reductase inhibitor that acts by interfering
Barrett 199663 Travelers 41 41 – – with folic-folinic acid systems. Proguanil is effective against the primary
Nasveld 200097 Austral. Defense – – 58 38 exoerythrocytic hepatic forms and is therefore a causal prophylactic. It
Hogh 2000a34 Travelers – 28 – 22 is also a slow-acting blood schizonticide and has sporonticidal effects
Overbosch 200162 Travelers 68 – – 71 against P. falciparum.
Schlagenhauf 200319 Travelers 88 86 84 82
a
Drug associated. Efficacy and Drug Resistance.  Chloroquine-resistant malaria began
A+P, Atovaquone/proguanil; C+P, chloroquine/proguanil; DX, to appear in Southeast Asia and South America in 1960 and reached
doxycycline; MQ, mefloquine. East Africa in 1978 and West Africa in 1985. Proguanil-resistant P.
148 SECTION 4 Malaria

TABLE 15.5  Antimalarial Drugs, Doses, and Adverse Effects (Listed Alphabetically) (See Text
for Contraindications)
Generic Name Trade Name Packaging Adult Dose Pediatric Dose Adverse Effects
Atovaquone/proguanil Malarone 250 mg atovaquone 1 tablet daily (see See textb Nausea, vomiting, abdominal pain,
and 100 mg text)a 5–8 kg: 12 pediatric tablet diarrhea, increased transaminases,
proguanil (adult 8–10 kg: 3 4 pediatric tablet seizures, rash
tablet) 10–20 kg: 1 pediatric tablet
20–30 kg: 2 pediatric tablets
30–40 kg: 3 pediatric tablets
>40 kg: 1 adult tablet
Chloroquinec Aralen 150-mg base 300-mg base once 5-mg base once weekly Pruritus in black-skinned individuals,
phosphate or Avochlot weeklya 5–6 kg: 25-mg base nausea, headache, skin eruptions,
sulfate Nivaquine 7–10 kg: 50-mg base reversible corneal opacity, nail and
Resochia 11–14 kg: 75-mg base mucous membrane discoloration,
15–18 kg: 100-mg base nerve deafness, photophobia,
19–24 kg: 125-mg base myopathy, retinopathy with daily
25–35 kg: 200-mg base use, blood dyscrasias, psychosis,
36–50 kg: 250-mg base seizures, alopecia
>50 kg or if ≥14 years: 300-mg
base
Doxycycline Vibramycin 100 mg 100 mg once dailya 1.5 mg/kg once daily (max Gastrointestinal upset, vaginal
Vibra-Tabs 100 mg daily) candidiasis, photosensitivity,
Doryx <25 kg or if <8 years: allergic reactions, blood
contraindicated dyscrasias, azotemia in renal
25–35 kg: 50 mg diseases, hepatitis
36–50 kg: 75 mg
>50 kg or if ≥14 years: 100 mg
Mefloquine Lariam 250-mg base (salt 250-mg base once <5 kg: no data Dizziness, diarrhea, nausea, vivid
Mephaquin in USA) weeklya 5–15 kg: 5 mg/kg once weekly dreams, nightmares, irritability,
15–19 kg: 1/4 tablet mood alterations, headache,
20–30 kg: 1/2 tablet insomnia, anxiety, seizures,
31–45 kg: 3/4 tablet psychosis
>45 kg: 1 tablet once weekly
Primaquine 15-mg base 30-mg base/day 0.5-mg base/day to max of GI upset, hemolysis in G6PD
Terminal prophylaxis 30-mg base/day deficiency, methemoglobinemia
or radical cure: Terminal prophylaxis or radical
15-mg base/day cure: 0.3-mg base/kg per day
for 14 daysd for 14 dayse
Proguanil Paludrine 100 mg 200 mg daily: Note: 5–8 kg: 25 mg (1/4 tablet) Anorexia, nausea, mouth ulcers
Not recommended 9–16 kg: 50 mg (1/2 tablet)
as a single agent 7–24 kg: 75 mg (3/4 tablet)
for prophylaxis 25–35 kg: 100 mg (1 tablet)
36–50 kg: 150 mg (1 1/2 tablets)
>50 kg or if ≥14 years: 200 mg
(2 tablets)
a
Dose for chemoprophylaxis.
b
In the United States and Europe, a pediatric formulation is available (quarter strength = 62.5 mg atovaquone and 25 mg proguanil). CDC
sanctions atovaquone/proguanil for infants >5 kg. WHO allows it for infants weighing >11 kg.
c
Chloroquine sulfate (Nivaquine) is not available in the United States and Canada, but is available in most malaria-endemic countries in both
tablet and syrup form.
d
Doses are increased to 30 mg-base/day for primaquine-resistant P. vivax.
e
Doses are increased to 0.5-mg base/kg per day for primaquine-resistant or tolerant P vivax.

falciparum is widespread, and this agent is not conventionally recom-
mended as a monoprophylaxis. It is believed that resistance prevents
access of chloroquine to the digestive process in the parasite’s lysosome,
and this process is modulated primarily by mutations in the gene PfCRT,
which encodes a transmembrane digestive vacuole protein. Mutations
in PfCRT permit the parasite to persist in chloroquine concentrations
that kill sensitive parasites.27,28 Some investigators suggest that
chloroquine-sensitive, wild-type P. falciparum is returning in parts of
Africa. A recent trial in Mozambique found that chloroquine cleared
89% of P. falciparum infections, and that only 1/108 P. falciparum isolates
carried the pfcrt K76E mutation,29 which could indicate that the dis-
continuation of chloroquine use since the early 1990s has perhaps
 CHAPTER 15  Malaria Chemoprophylaxis
Anopheles
Primary
Liver cycle
-Atovaquone
-Primaquine
-Tafenoquine
(limited: Azithromycin,
Doxycycline, Proguanil)
Relapse
-Primaquine, Tafenoquine
primary
attack
Erythrocytic cycle
- Atovaquone
- Azithromycin
- Chloroquine
- Doxycycline
- Mefloquine
Erythrocytic
- Proguanil
- Tafenoquine
FIG. 15.1  The lifecycle of malaria parasites in the human host, showing sites of action of antimalarial drugs.
resulted in a reversal to a chloroquine-sensitive, wild-type P. falciparum.
Chloroquine-resistant P. vivax was reported in 1989 in New Guinea
and later elsewhere in Oceania, India, Asia, and parts of South America,
and because of the widespread distribution of P. vivax (estimated exposure
of 2.85 billion people) increasing chloroquine-resistant P. vivax will
have far-reaching public health implications.30 A recent study from
India, looking at the PvCRT-o (P. vivax chloroquine resistance
transporter-o) and PvMDR-1 (P. vivax multidrug resistance-1) genes
classified 23% of P. vivax as potentially resistant to chloroquine.31
A study from Myanmar found a low chloroquine clinical failure,
but genes potentially coding for chloroquine-resistant phenotypes—
pvcrt-O ‘AAG’ insertion and the pvmdr1 mutation (Y976F)—were
common in southern and central Myanmar.32 A study from Thailand
found that chloroquine cured 99% of P. vivax cases.33 A randomized,
controlled trial from Brazil comparing treatment of P. vivax with
artesunate-amodiaquine and chloroquine found treatment failure of
chloroquine in 11.5% of cases.34 A recent review of clinical trials including
chloroquine in at least one arm found chloroquine P. vivax resistance
in 59 (45%) sites in 15 endemic areas.31
Tolerability.  One RCT23 showed poor tolerability of chloroquine/
proguanil compared to doxycycline, mefloquine, or atovaquone/proguanil.
Serious Adverse Event (AE), such as psychotic episodes, have been
reported in <1/13,600 users of the chloroquine/proguanil regimen.35,36
Keratopathy, retinopathy, and visual disorders have been reported in
149
Relapse
-Primaquine
-Tafenoquine
Anopheles
relapse
cycle
Gametocyte
(mature P. falciparum)
- Primaquine, Tafenoquine
chloroquine users,22 particularly during long-term use of the drug. Six
ophthalmologic checks are recommended once every 6 months, par-
ticularly when the cumulative dose exceeds 100 g.
Contraindications, Precautions, and Drug Interactions41.  Accord-
ing to the manufacturer, chloroquine is contraindicated in persons
hypersensitive to the 4-aminoquinoline compounds and in G6PD-
deficient individuals (although significant hemolysis is rare when given
at prophylactic and therapeutic doses). Other contraindications are
preexisting retinopathy, diseases of the central nervous system (CNS),
myasthenia gravis, disorders of the blood-producing organs, and a history
of epilepsy or psychosis. Dosage reduction may be required in patients
with hepatic function impairments. Chloroquine and chloroquine/
proguanil may be used in pregnancy. During lactation the drug is
present in breast milk, but not in sufficient quantities to either harm
or protect the infant. There is no known absolute contraindication
for proguanil. Concomitant use of chloroquine and proguanil has
been shown to increase the incidence of mouth ulcers. Administra-
tion of the oral live typhoid vaccine and live cholera vaccine should
be completed 3 days before chloroquine use, and chloroquine may
suppress the antibody response to intradermal primary preexposure
rabies vaccine. Other possible interactions can occur with gold salts,
monoamine oxidase (MAO) inhibitors, digoxin, and corticosteroids. The
activity of methotrexate and other folic acid antagonists is increased by
chloroquine use.
150 SECTION 4 Malaria

Travel to a country in No
No prophylaxis
which malaria is endemic?

Yes

Malaria in area No
No prophylaxis
of travel?

Yes

Prevention of
mosquito bites

Plus

Chloroquine- Yes
Chloroquine, provided no contraindications
sensitive area?

No

Mefloquine- Yes Pregnancy or

resistant area? children <8 years?
No Yes

Doxycycline or If pregnant Defer travel

No Atovaquone +
proguanil
If child >5 kg Use Atovaquone
and proguanil

Based on contraindications*†, duration of travel, cost and other factors choose between:

Atovaquone/proguanil Doxycycline Mefloquine

Rule out contraindications Rule out contraindications Rule out contraindications
such as such as such as
stay >28 days † Age <8 years history of epilepsy
pregnancy pregnancy or psychiatric disorder

Pregnancy?
No Yes

Mefloquine Defer travel if possible

or Mefloquine (allowed in all trimesters for high risk areas)
Atovaquone + proguanil or
or Chloroquine + proguanil
Doxycycline (safe but less effective)

FIG. 15.2  Malaria prophylaxis choices. (*Note: This figure is intended as a visual aid only. Please refer to
text and product/package insert monograph for other important details regarding contraindications, precautions,
and drug tolerability.)

Indications and Administration.  Chloroquine is the drug of choice
in the few malaria-endemic areas free of chloroquine-resistant P. fal-
ciparum (CRPf) malaria. Combining chloroquine and proguanil is an
option for CRPf when other first line antimalarials are contraindicated,
but this combined regimen is now rarely used. Pediatric preparations
are available (see Table 15.5).
Mefloquine
Description, Pharmacology, and Mode of Action.  Mefloquine was
selected in the 1960s by the Walter Reed Army Institute of Research
from nearly 300 quinoline methanol compounds for further inves-
tigation because of its high antimalarial activity in animal models.37
Today, mefloquine is used clinically as a 50 : 50 racemic mixture of the
erythro isomers. The commercial form is available as tablets containing
250 mg mefloquine base. The mefloquine formulation available in the
United States contains 250 mg mefloquine hydrochloride (equivalent
to 228 mg mefloquine base). Mefloquine has been available for malaria
chemoprophylaxis in nonimmunes since 1985 in Europe, and since
1990 in the United States, and has been used by >35 million travelers
for this indication.
Mefloquine is a potent, long-acting blood schizontocide and is
effective against all malarial species,38 including the fifth species39
Plasmodium knowlesi. The exact mechanism of activity is unclear, but
mefloquine is thought to compete with the complexing protein for
heme binding and the resulting drug-heme complex is toxic to the
parasite.40
Efficacy and Drug Resistance.  Mefloquine is recognized as a highly
effective malaria chemoprophylaxis for nonimmune travelers to high-risk
CRPf areas. The first report of mefloquine resistance came from Thailand
in 1982, and this region remains a focus of resistance, particularly on
the Thai-Cambodian and Thai-Burmese borders, where prophylaxis
breakdown has been observed. As reviewed by Mockenhaupt,41 reports
of mefloquine treatment or prophylactic failures have been reported
 CHAPTER 15  Malaria Chemoprophylaxis
from distinct foci in Asia and, to a lesser extent, from Africa and the
Amazon Basin in South America. Studies in 1993 showed high efficacy
of mefloquine in travelers.42 Long-term prophylaxis with mefloquine
proved highly effective in Peace Corps volunteers stationed in sub-Saharan
Africa, with an incidence of 0.2 infections/month in 100 volunteers.
Weekly mefloquine was considered 94% more effective than prophylaxis
with chloroquine and 86% more effective than prophylaxis with the
chloroquine/proguanil combination.42 Mefloquine was shown to be highly
efficacious (100%) in the prevention of malaria in Indonesian soldiers in
Papua, and Rieckmann43 found mefloquine to be 100% effective against P.
falciparum in Australian soldiers deployed in Papua New Guinea (PNG).
Pergallo44 reported on the effective use of mefloquine by Italian troops
in Mozambique in 1992–1994. When chloroquine/proguanil was the
recommended regimen, an attack rate of 17 cases/1000 soldiers per month
was noted. The rate dropped significantly to 1.8 cases/1000 soldiers per
month when chloroquine/proguanil was replaced by mefloquine. The
effectiveness of long-term mefloquine in the United Nations peacekeep-
ing forces in Cambodia in 1993 was 91.4%.45 Conversely, mefloquine
was found to be incompletely effective in the prevention of malaria in
Dutch Marines in Western Cambodia in 1992–1993. The attack rate in
Marines varied significantly according to the geographic location of the
battalions. Of 260 persons assigned to the Sok San area, 43 developed
malaria (16%, 6.4/1000 person-weeks) compared to 21 of 2029 stationed
elsewhere (1%, 0.5/1000 person-weeks). Mefloquine-resistant parasites
were isolated from Dutch and Khmer patients.46 The use of antimalarials
by American troops during Operation Restore Hope in Somalia in
1992–1993 showed high prophylactic efficacy in mefloquine users.
Sanchez et al.47 reported the prophylactic efficacy in an uncontrolled
cross-sectional survey of troops at one location (Bale Dogle). Mefloquine
users had a malaria rate of 1.15 cases/10,000 person-weeks, compared to
5.49 cases/10,000 person-weeks in doxycycline users. From this and other
reports,48 mefloquine was shown to be more effective than doxycycline
in US troops deployed in Somalia. The lower efficacy of doxycycline
was attributed to poorer compliance. Mefloquine was shown to provide
a high degree of protection in Dutch servicemen (n =125) deployed
as part of a disaster relief operation to Goma, Zaire (1994). Despite
evidence of exposure to P. falciparum as shown by the presence of
circumsporozoite antibodies in 11.2% of the group, none developed
overt malaria that was attributed to their use of mefloquine prophy-
laxis.49 In a German population-based case control study, mefloquine
was considered to be 94.5% effective in preventing malaria in tourists
to Kenya.50
Prophylactic Failures and Resistance.  The molecular basis of
mefloquine resistance is currently unknown but may be the result of
mutation or amplification of certain gene products such as Pgh1, an
energy-dependent transporter encoded by the multidrug-resistant (mdr)
homolog Pfmdr1. Studies demonstrate that mutations in pfmdr1 may
confer mefloquine resistance to sensitive parasites.51 Penfluridol, a
psychotropic drug, has been reported to reverse mefloquine resistance
in P. falciparum in vitro.52
In many geographic regions, mapping of prophylactic failures, mainly
in nonimmune individuals, has been used to detect early resistance
development, although it should be emphasized that prophylactic failures
do not prove resistance. Mefloquine blood concentrations of 620 ng/
mL are generally considered necessary to achieve 95% prophylactic
efficacy. As defined by Lobel, a prophylactic failure is a confirmed P.
falciparum infection in persons with mefloquine blood levels in excess
of this protective level.53 Using this definition, an analysis of 44 confirmed
P. falciparum cases acquired in sub-Saharan Africa53 showed five vol-
unteers with mefloquine-resistant P. falciparum malaria. Other confirmed
cases were attributed to poor compliance, and the authors concluded
151
Chemoprophylaxis choices 201X
Priority antimalarial
for chloroquinine
resistant Pf (CRPF)
Melfloquine* Atovaquone/proguanil* Doxycycline
250 mg weekly 250 mg/100 mg daily 100 mg daily
Alternative options
for chloroquinine
resistant Pf (CRPF)
Primaquine Tafenoquine (pipeline)
(United States, Canada) 200 mg daily for 3 days
30 mg daily followed by 200 mg weekly
FIG. 15.3  Priority antimalarials—the options for chemoprophylaxis.
that prevalence of mefloquine-resistant malaria in sub-Saharan Africa
is still low. With regard to P. vivax, it has been hypothesized that the P.
vivax Pvmdr1 gene amplification results in reduced susceptibility to
mefloquine, but one study did not find that mutations in the Pvmdr1
gene decreased P. vivax sensitivity to mefloquine.54
Plasmodium ovale, P. malariae, and P. knowlesi remain fully susceptible
to mefloquine while noting the need for primaquine to eliminate the
hypnozoites of P. ovale.
With regard to cross-resistance, there is recent evidence that exposure
of parasite populations to antimalarial drug (Fig. 15.3) pressure may
select for resistance not only to the drug providing the pressure, but
also to other drugs. This was clearly illustrated in the northern part of
Cameroon, West Africa, where the detection of a high level of resistance
to mefloquine was attributed to cross-resistance with quinine,55 a
drug that had been widely used for therapy in the area. Resistance to
mefloquine appears to be distinct from chloroquine resistance, as shown
by the activity of mefloquine against CRPf and by the inefficacy of
verapamil to reverse mefloquine resistance, although it does modulate
chloroquine resistance. Moreover, in vitro studies have documented an
inverse relationship between chloroquine and mefloquine resistance.
Mefloquine resistance is, however, associated with halofantrine resis-
tance56 and quinine resistance.55,56 Innate resistance (i.e., the existence
of small subpopulations of intrinsically resistant malarial parasites
within any infecting parasite biomass) is still controversial and may to
some extent be explained by cross-resistance to other drugs. Sporadic
reports from tropical Africa describe single travelers with P. falciparum
malaria despite apparent compliance with mefloquine.57 This has been
attributed to inadequate dosing in heavy individuals. Mefloquine remains
an effective drug for chemoprophylaxis against P. falciparum malaria in
tropical Africa.
Tolerability.  There is considerable controversy among international
experts regarding the tolerability of mefloquine prophylaxis, and several
new restrictions have been imposed.58 On July 29, 2013, the US Food
and Drug Administration (FDA) issued “a boxed warning” announcement
about strengthened and updated restrictions regarding mefloquine and
the risk of neuropsychiatric adverse events. Following this, in Europe,
in 2014, the European Medicines Agency (EMA) issued recommendations
152 SECTION 4 Malaria
on strengthened warnings, prescribing checklists and updates to the
product information of mefloquine.58 These new restrictions mandate
careful prescribing of the drug and demand that prescribers check for
contraindications such as depression or other psychiatric illness and
inform mefloquine users of possible AE.38,58 Some important new studies
have examined specific safety aspects of mefloquine and other antimalari-
als. Schneider et al.21 evaluated eye disorders using the UK General
Practice Research Database. Compared to nonusers of antimalarials,
the adjusted odds ratio with 95% confidence interval (CI) in the nested
case control analysis for users of mefloquine, chloroquine and/or
proguanil, or atovaquone/proguanil were 1.33 (1.01–1.75), 1.61
(1.06–2.45), and 1.25 (1.03–1.52), respectively, indicating that ocular
toxicity is an issue with many antimalarials.
Regarding tolerability, an overview of the studies and databases
comparing the use of malaria chemoprophylactic agents in travelers
(see Tables 15.2, 15.3, and 15.4) shows largely disparate results owing
to differing designs, definitions, and methodologies as well as differing
study populations. Regarding the reporting of any AE, the incidence
during the use of mefloquine lies in the range of 24%–88%, and when
there is a comparator, is usually equivalent to the incidence reported for
almost all chemoprophylactic regimens. A double-blind study comparing
all regimens showed that the tolerability of atovaquone/proguanil and
doxycycline is superior to that of mefloquine, and women in particular
were significantly more likely to experience neuropsychiatric-type AE.23
Moderate/Severe Adverse Events.  Although often a subjective
report by the traveler, when some measure of severity is applied to AE
reporting it appears that 11%–17%23,59–66 of travelers using mefloquine
are to some extent incapacitated by adverse events. The extent of this
incapacitation is often difficult to quantify, and a good measure of the
impact of adverse events is the extent of chemoprophylaxis curtailment.
In a recent study67 comparing tolerability in deployed soldiers using
mefloquine or doxycycline, significantly fewer mefloquine users (12.6%)
reported that one or more adverse events had impacted upon their
ability to do their job, compared to 22.2% of doxycycline users.
In a study of 5120 Italian soldiers using either chloroquine/proguanil
(C+P) or mefloquine, deployed in Somalia and Mozambique in
1992–1994, the rate of prophylaxis discontinuation in the C+P users
was 1.5%, compared to a significantly lower rate of discontinuation in
mefloquine users (0.9%).44 This contrasts with a study comparing
mefloquine and atovaquone/proguanil (A+P), where subjects receiving
the A+P combination regimen had a significantly lower rate of drug-
related AE that caused discontinuation of prophylaxis (5% versus 1%).59
A four-arm, controlled tolerability study showed intermediate withdrawal
rates for mefloquine (3.9%) and doxycycline (3.9%) versus chloroquine/
proguanil (5.2%) compared with atovaquone/proguanil, which had the
lowest withdrawal rate (1.8%).23
Serious Adverse Events.  These are adverse events that constitute
an apparent threat to life, which require prolong hospitalization or
result in severe disability.68 With mefloquine the incidence range is
estimated between 1/6000 and 1/10,600,35,64,69 compared to a rate in
chloroquine users of 1/13,600. In a retrospective cohort analysis, serious
neuropsychiatric AE were noted for 1/607 mefloquine users versus 1/1181
chloroquine/proguanil users.60
Neuropsychiatric Adverse Events.  This is the main area of con-
troversy with regard to the tolerability of mefloquine. Neuropsychiatric
disorders include two broad categories of symptoms, namely central
and peripheral nervous system disorders (including headache, diz-
ziness, vertigo, seizures) and psychiatric disorders (including major
psychiatric disorders, affective disorders, anxiety, sleep disturbances). The
neuropsychiatric profile of adverse events occurring with mefloquine has
been previously shown.23,64–66 However, a large database analysis showed
that the use of mefloquine or any other antimalarials is associated with
neuropsychiatric events and that these cannot be specifically attributed
to mefloquine.70 No large prospective controlled study has confirmed
the true incidence of neuropsychiatric events during prophylaxis. The
thrust of the new safety communications58 from the FDA and EMA is
to reinforce communication on the potential risk of such adverse events
occurring and their possible long-term duration. However even in the
literature, except for occasional case reports, data on the duration and
persistence of mefloquine-related AE are lacking. One Danish study
examined long-term outcomes of neuropsychiatric events.71 A recent
study from Tan et al. on illness in Peace Corps volunteers who used
malaria prophylaxis found that the prevalence of most diseases at long-
term follow-up was similar in those exposed to malaria prophylaxis
compared to those not exposed to prophylaxis. This also held true
for psychiatric-type diagnoses in users of all antimalarials including
prescreened mefloquine users.72
Two controlled studies have shown a significant excess of neuro-
psychiatric events in mefloquine users versus comparators.23,59 The
precise role of antimalarial drugs in neuropsychiatric adverse events is
difficult to define. In terms of all AE, studies have shown that women
are significantly more likely to experience them.23,59,73,74 The AE bias to
women might be due to reporting bias, greater compliance with prescrip-
tion,74 or to gender-related differences in drug absorption, metabolism,
or CNS distribution. With respect to dose-related toxicity, there appears
to be an association between low body weight and a relatively high risk
of developing AE during malaria prophylaxis. Some experts recommend
using a split dose (a half tablet twice weekly) for women with low body
weight. Anecdotal reports suggest positive experience with this approach,
but no published pharmacokinetic data are available. Computer simula-
tions suggest that reduced dosage in women would be effective and
might result in improved tolerability. An earlier tolerability study aimed
to correlate nonserious AE occurring during routine chemoprophylaxis
with concentrations of racemic mefloquine, its enantiomers, or the
carboxylic acid metabolite.63 The disposition of mefloquine was found
to be highly selective, but neither the concentrations of enantiomers,
nor total mefloquine, nor metabolite were found to be significantly
related to the occurrence of nonserious AE. A role has been suggested
for the concomitant use of mefloquine and recreational drugs66 or an
interaction between mefloquine and large quantities of alcohol,75 although
concomitant use of small quantities of alcohol does not appear to
adversely affect tolerability.76 Children tolerate mefloquine well,77 as do
elderly travelers who report significantly fewer AE than younger
counterparts.78 One report suggests that subjects with AE have slower
elimination of mefloquine than the population in general. Some
researchers have used animal models to propose mechanisms that may
explain the neuropsychiatric profile of adverse events associated with
mefloquine. The phenomenon of “connexin blockade” by mefloquine
has been proposed as a possible explanation for some mefloquine-
associated adverse events.79 Careful screening of travelers, with particular
attention to contraindications such as personal or family history of
epilepsy/seizures or psychiatric disorders, should minimize the occurrence
of serious AE. Travel health advisors now recommend starting mefloquine
3 weeks before travel to allow for adverse event screening. The positive
outcome of the new safety recommendations58 is that screening prior
to mefloquine prescription will be mandatory and follow a checklist
format. This should ensure that contraindications are observed, which
in the past has not always been the case.
Contraindications, Precautions, and Drug Interactions.  Following
strengthened restrictions by the FDA and the EMA,58 the package insert
 CHAPTER 15  Malaria Chemoprophylaxis
for mefloquine has been updated. Mefloquine is contraindicated in
persons
• known to be hypersensitive to mefloquine or related compounds
(e.g., quinine, quinidine)
• who currently suffer or who have suffered at any time from depression,
generalized anxiety disorder, psychosis, schizophrenia, suicide
attempts, suicidal thoughts, self-endangering tendencies, or any other
psychiatric disorder or convulsions of any origin
• with severe impairment of liver function
New contraindications
• A history of blackwater fever is now a contraindication.
• Concomitant use of halofantrine is a contraindication and in some
countries, including Germany, concomitant use of ketoconazole has
been added as a contraindication.
New precautions.  Prescribers need to highlight the risk of neuro-
psychiatric adverse events that can occur during the use of mefloquine,
provide a detailed description of possible adverse events and their
duration, and instruct the user to read the package information leaflet
and provide the user an alert card.
Pregnancy.  Most authorities now allow the use of mefloquine in
all trimesters if travel cannot be deferred and if the expected benefit
outweighs the risk. A drug safety database analysis of mefloquine exposure
in the prenatal period and during pregnancy showed that the birth
defect prevalence and fetal loss in maternal, prospectively monitored
cases were comparable to background rates.80 Inadvertent pregnancy
while using mefloquine is not considered grounds for pregnancy termina-
tion. Mefloquine is secreted into breast milk in small quantities. The
effect, if any, on breastfed infants is unknown, but the amount of drug
secreted in the breast milk is inadequate to protect an infant from
malaria so breastfed babies require their own chemoprophylaxis.
A retrospective analysis of a database of antimalarial tolerability
data showed that comedications commonly used by travelers have had
no significant clinical impact on the safety of prophylaxis with meflo-
quine.81 The coadministration of mefloquine with cardioactive drugs
might contribute to the prolongation of QTc intervals, although in the
light of the information currently available coadministration of meflo-
quine with such drugs is not contraindicated but should be monitored.
Vaccination with oral live typhoid or cholera vaccines should be
completed at least 3 days before the first dose of mefloquine. Caution
is indicated in persons performing tasks requiring fine coordination,
but a review of performance impact of mefloquine82,83 suggests that if
mefloquine is tolerated by an individual then his or her performance
is not undermined by use of the drug.
Indications and Administration. Mefloquine is effective in the
prevention of CRPf malaria, except in clearly defined Thai border regions
of multidrug resistance. It is a priority antimalarial for screened travelers,
with no contraindications, to high-risk malaria-endemic areas. The
recommended adult dose for chemoprophylaxis is 250 mg base weekly
as a single dose (US 228 mg base). Adults weighing <45 kg and children
>5 kg require a weekly dose of 5 mg base/kg (see Table 15.5). Loading
doses of mefloquine for last-minute travelers are no longer recommended
due to an increased risk of AE.
Mefloquine and its metabolite are not appreciably removed by
hemodialysis.84 No special dosage adjustments are indicated for dialysis
patients to achieve concentrations in plasma similar to those in healthy
volunteers.
Doxycycline
Description.  The tetracyclines form a class of broad-spectrum
antimicrobial agents. Doxycycline and minocycline were derived
semisynthetically in 1967 and 1972, respectively. In many countries
153
doxycycline is used “off-label” for malaria chemoprophylaxis. The only
FDA-approved indication for this class of agents is the use of doxycycline
for the prophylaxis of P. falciparum in short-term travelers (<4 months)
to drug-resistant areas.
Pharmacology and Mode of Action.  Tetracyclines, including doxy-
cycline, are relatively slow-acting schizonticidal agents and are therefore
not used alone for treatment. However, numerous studies have established
the efficacy of doxycycline as a solo chemoprophylactic agent against
P. vivax and P. falciparum malaria. In addition to its activity against the
erythrocytic stage of the parasite, doxycycline is thought to possess
some preerythrocytic (causal) activity. However, studies examining its
efficacy as a causal agent had unacceptably high failure rates, and to be
optimally effective doxycycline needs to be taken as a chemosuppressant
for 4 weeks after leaving a malaria-endemic area.85,86
The mechanism of action of tetracyclines in bacteria has been exam-
ined in detail and is presumed to be similar in protozoa. Tetracyclines
reversibly bind primarily to the 30S ribosomal subunit, thereby inhibiting
protein synthesis by preventing the incorporation of new amino acids
into the growing peptide chain.87 In addition, in P. falciparum malaria,
doxycycline has been shown to impair expression of apicoplast genes
required for parasite survival.87 Doxycycline has several advantages
over first-generation tetracyclines, including improved absorption, a
broader spectrum, a longer half-life, and an improved safety profile.
Doxycycline is well absorbed from the proximal small bowel (>90% oral
absorption), and in contrast to other tetracyclines its uptake does not
change significantly with food intake. Doxycycline may be taken with
food but should not be taken with milk. Doxycycline is highly protein
bound (93%), has a small volume of distribution (0.7 L/kg), and is lipid
soluble. These features may explain its high blood levels and prolonged
half-life, permitting a once-daily dosing regimen. Doxycycline has a
half-life of approximately 15–22 hours that is unaffected by renal impair-
ment. Doxycycline is eliminated in the urine unchanged by glomerular
filtration, and largely unchanged in the feces by biliary and GI secretion.
About 40% of the dose is eliminated in the urine in individuals with
normal kidney function, whereas those with renal dysfunction are able
to eliminate it via the liver-biliary-GI route.
Efficacy and Drug Resistance.  A number of randomized trials have
examined the efficacy of doxycycline as a chemoprophylactic against
Plasmodium spp.88–92 Four of these studies were randomized, double
blind, and placebo controlled. Two of these trials evaluated semiimmune
children or adults in Kenya, and three trials examined nonimmune
populations in Oceania. The reported protective efficacy in these trials
was excellent, ranging from 92% to 99% against P. falciparum and 98%
for primary P. vivax malaria. Doxycycline does not kill P. vivax hypno-
zoites and does not prevent relapses of P. vivax and P. ovale malaria. In
comparative trials in areas with CRPf malaria, doxycycline has been
shown to be equivalent to mefloquine and atovaquone-proguanil and
superior to azithromycin and chloroquine/proguanil.93–95 Parasite
resistance to doxycycline has not been reported to be an operational
problem in any malaria-endemic areas thus far, but prophylactic failures
are reported in association with poor adherence, missed doses, and
inadequate doses.96,97
No systematic studies of the efficacy of doxycycline for malaria
chemoprophylaxis has been performed. A study of 90 P. falciparum
isolates from 14 countries found that increases in copy numbers of P.
falciparum metabolite drug transporter gene (Pfmdt, PFE0825w) and
P. falciparum GTPase TetQ gene (PfTetQ, PFL1710c) are associated with
reduced susceptibility to doxycycline.98 The PftetQ KYNNNN motif
repeats have been associated with in vitro reduced susceptibility to
doxycycline.99
154 SECTION 4 Malaria
P. vivax.  A study from Ethiopia of Israeli travelers found that of
19 using doxycycline for prophylaxis, 10 developed malaria: 9 P. vivax
and 1 a mixed-infection P. vivax and P. falciparum.100 Another study
comparing mefloquine and doxycycline in Indonesian solders found
no difference in the protection against P. falciparum and P. vivax,101
and the difference between the two studies could be compliance.
P. ovale, P. malariae, and P. knowlesi.  A study of 328 incident P.
ovale infections in French servicemen stationed in tropical Africa found
that 295 (92%) had taken doxycycline as prophylaxis, 15 (5%)
chloroquine-proguanil, and 10 (3%) mefloquine. The self-declared
compliance overall was 53%.102 No data exist regarding the efficacy of
doxycycline for the prevention of P. malariae and P. knowlesi.
Tolerability.  The most commonly reported adverse events related to
doxycycline use are GI effects (4%–33%), including nausea, vomiting,
abdominal pain, and diarrhea. These adverse effects are less frequent
with doxycycline than with other tetracyclines. Esophageal ulceration
is a rare but well-described AE associated with doxycycline use that
generally presents with retrosternal burning and odynophagia 1–7 days
after therapy is initiated.52,100 Limited data suggest that doxycycline
monohydrate and enteric-coated hyclate formulations may have fewer
GI adverse events than regular hyclate formulations.97,98
Dermatologic reactions are also a frequent adverse event associated
with doxycycline use. These reactions range from mild paresthesias or
exaggerated sunburn in exposed skin to photo-onycholysis (sun-induced
separation of nails), severe erythema, bulla formation, and (rarely)
Stevens-Johnson syndrome.97 The reported rate of photosensitivity varies
from <7% to 21% or more of users, and the reaction is mild in the major-
ity of cases.97,101 The risk of photosensitivity may be reduced by the use
of appropriate sunscreens (sun protection factor [SPF] >15 and protective
against both ultraviolet A [UVA] and ultraviolet B [UVB] radiation).97
Although doxycycline has a lesser effect on normal bacterial flora
than other tetracyclines, it still increases the risk of oral and vaginal
candidiasis in predisposed individuals. Travelers with a history of these
problems who are prescribed doxycycline should be advised to carry
an appropriate treatment course of antifungal therapy.
Other uncommon adverse events occasionally attributed to doxy-
cycline include dizziness, lightheadedness, darkening or discoloration
of the tongue, and (rarely) hepatotoxicity, pancreatitis, or benign
intracranial hypertension.97
Overall, a number of comparative studies have shown that doxycycline
used as a chemoprophylactic agent is generally well tolerated and has
relatively few reported side effects. In clinical trials, doxycycline was
tolerated as well as or better than placebo or the comparator drug,23,97
with few serious AE reported. Randomized control trials comparing
the tolerability of mefloquine and doxycycline in soldiers deployed in
Thailand, and primaquine, doxycycline, proguanil/chloroquine, and
mefloquine compared with placebo in semiimmune children in Kenya,
found no significant differences in tolerability between these agents.94
Ohrt and colleagues compared mefloquine and doxycycline in a random-
ized placebo-controlled field trial in nonimmune soldiers in Papua
(Irian Jaya). In this trial both drugs were well tolerated, but doxycycline
was better tolerated than mefloquine or placebo with respect to the
frequency of reported symptoms.101 The authors attributed this to the
potential of doxycycline to prevent other infectious processes. Anderson
and colleagues compared doxycycline and azithromycin in a field trial
in semiimmune adults in western Kenya.93 Both drugs were well tolerated
compared with placebo, but there was one case of doxycycline withdrawal
due to recurrent vaginitis. There were no significant differences observed
in adverse event profiles between the treatment arms, except that
azithromycin was protective against dysentery. A randomized comparative
trial of antimalarial tolerability reported that doxycycline monohydrate
was the best tolerated of the four regimens (compared to mefloquine,
atovaquone/proguanil, and chloroquine/proguanil).23
Adherence with doxycycline, despite its daily dosing schedule, has
been reported to be relatively good in studies examining short-term
use. Estimating adherence rates in travelers is difficult because such
studies require close daily monitoring. Ohrt and colleagues extended
their initial comparative study of doxycycline and mefloquine but did
not enforce adherence as they did in the first phase of the study.101 This
resulted in a drop in the protective efficacy of doxycycline from 99%
(95% CI 94%–100%) to 89% (95% CI 78%–96%) against all malaria,
suggesting a decrease in drug adherence if close monitoring is not done.
Similar experience of declining effectiveness over time due to adherence
issues has been reported by the US military deployed in Somalia and
in Dutch troops deployed in Cambodia. US troops in Somalia using
doxycycline had fivefold higher attack rates by P. falciparum than did
mefloquine users. These differences were attributed to poor adherence
with daily use rather than to doxycycline resistance. Collectively these
studies suggest that adherence with daily doxycycline may be challenging,
especially for long-term travelers.
Contraindications, Precautions, and Drug Interactions.  Doxycy-
cline administration is not recommended in the following situations:
• Allergy or hypersensitivity to doxycycline or any member of the
tetracycline class.
• Infants and children <8 years of age. Tetracyclines bind calcium and
may cause permanent yellow-brown discoloration of teeth, damage
to tooth enamel, and impairment of skeletal growth in this population.
Doxycycline binds calcium less than other tetracyclines, and short
courses of doxycycline (such as in the treatment of Rocky Mountain
spotted fever) have not been reported to cause clinically significant
staining of teeth.103
• Pregnancy. Doxycycline crosses the placenta and therefore may cause
permanent discoloration of teeth, damage to tooth enamel, and
impairment of skeletal growth in the fetus (category D drug). Some
experts (United Kingdom and Swedish) allow the use of doxycycline
prophylaxis in early pregnancy (first trimester) if other options are
contraindicated.
• Breastfeeding. Doxycycline is excreted in breast milk and therefore
may cause permanent discoloration of teeth, damage to tooth enamel,
impairment of skeletal growth, and photosensitivity in breastfed
infants.
Precautions should be taken when using doxycycline in individuals
who are susceptible to photosensitivity reactions or who have vaginal
yeast infections or thrush. In addition, certain susceptible individuals
with asthma may experience an allergic-type reaction to sulfite, which
is formed with the oxidation of doxycycline calcium oral suspension.
Doxycycline is partially metabolized by the liver; in individuals with
significant hepatic dysfunction there may be a prolonged half-life, and
a dose adjustment may be required.
The safety of long-term doxycycline use (>3 months) has not been
adequately studied.103,104 Because lower doses of doxycycline and
minocycline (a related tetracycline) are frequently used for extended
periods to treat acne, it has been presumed that long-term use of doxy-
cycline at an adult dose of 100 mg/day is safe. However, serious adverse
events, including autoimmune hepatitis, fulminant hepatic failure, a
serum sickness–like illness, and drug-induced lupus erythematosus,
have been reported with the use of minocycline for acne.105 It is not
known whether doxycycline causes similar adverse events, but doxycycline
was not associated with an increased risk of hepatotoxicity in a single
reported case-control study.106 A number of potentially important drug
interactions have been associated with doxycycline use,97 including those
involving the following drugs and substances:
 CHAPTER 15  Malaria Chemoprophylaxis
• Antacids containing divalent or trivalent cations (calcium, aluminum,
and magnesium). Doxycycline binds cations, and concomitant
administration of antacids will reduce serum levels of doxycycline.
• Doxycycline should not be administered with milk and it is recom-
mended to separate doxycycline and ingestion of dairy products by
2–3 hours. This recommendation is based on the fact that milk
decreases the absorption of doxycycline and other tetracyclines
because of chelation between the calcium (Ca++) in the milk and
doxycycline. One early study administered doxycycline with either
water or milk. Simultaneous ingestion of milk diminished the
doxycycline peak plasma concentration by 24%.107
• Oral iron, bismuth salts, calcium, cholestyramine or colestipol, and
laxatives that contain magnesium. Concomitant ingestion of these
compounds may reduce doxycycline absorption. These agents should
not be taken within 1–3 hours of doxycycline ingestion.
• Barbiturates, phenytoin, and carbamazepine. These drugs induce
hepatic microsomal enzyme activity and, if used concurrently with
doxycycline, may reduce doxycycline serum levels and half-life and
may necessitate a dosage adjustment.
• Oral contraceptives. Older literature reported that concurrent use
of doxycycline with estrogen-containing birth control pills might
result in decreased contraceptive efficacy and recommended an
additional method of birth control. However, there are few examples
of oral contraceptive failure attributable to doxycycline use, and
serum hormone levels in patients taking oral contraceptives have
been reported to be unaffected by coadministration of doxycycline.
Current evidence97 suggests that doxycycline can be used concurrently
with oral contraceptives without leading to a higher rate of contracep-
tive failure.97,108
• Anticoagulants. The anticoagulant activity of oral anticoagulants
may be enhanced with concurrent use of doxycycline. Close monitor-
ing of prothrombin time is advised if these drugs are used together.
• Vitamin A. The use of tetracyclines with vitamin A has been reported
to be associated with benign intracranial hypertension.
Indications and Administration.  Doxycycline is a priority first line
antimalarial for prevention of mefloquine-resistant P. falciparum malaria
(evening or overnight exposure in rural border areas of Thailand with
Myanmar [Burma] or Cambodia), or as an alternative to mefloquine
or atovaquone/proguanil for the prevention of CRPf malaria. Doxycycline
has a half-life that permits once-daily dosing. The dosage of doxycycline
recommended for chemoprophylaxis against drug-sensitive and drug-
resistant malaria is 2 mg base/kg of body weight, up to 100 mg base
daily (see Table 15.5). Studies have examined lower-dose regimens, but
such regimens have provided inadequate protection.90,91 Doxycycline
should be taken once daily, beginning 1–2 days before entering a malarial
area, and should be continued daily while there. Because of its poor
causal effect, it must be continued for 4 weeks after leaving the risk
area. To reduce the occurrence of GI adverse events, it should be taken
in an upright position with food and at least 100 mL of fluid or use
the monohydrate form of the drug.
Atovaquone/Proguanil
AP, a fixed drug combination, is a priority antimalarial for the prophylaxis
of P. falciparum malaria.109 AP was first approved in Switzerland in
August 1997 (as Malarone). Generic preparations are now also
available.
Description.  AP is effective for both the prevention and treatment
of malaria. Atovaquone is a hydroxynaphthoquinone compound and,
combined with proguanil, an antifolate drug, works synergistically
against the erythrocytic stages of all the Plasmodia parasites and the
155
liver stage (causal prophylaxis) of P. falciparum.109–111 AP is not active
against hypnozoites in P. vivax and P. ovale and does not prevent relapse
infections.
Pharmacology and Mode of Action.  Atovaquone acts by inhibiting
parasite mitochondrial electron transport at the level of the cytochrome
bc1 complex, and collapses mitochondrial membrane potential.112 The
plasmodial electron transport system is 1000 times more sensitive to
atovaquone than the mammalian electron transport system, which likely
explains the selective action and limited side effects of this drug.
Proguanil, as described, is metabolized to cycloguanil, which acts by
inhibiting dihydrofolate reductase (DHFR). The inhibition of DHFR
impedes the synthesis of folate cofactors required for parasite DNA
synthesis. However, it appears that the mechanism of synergy of proguanil
with atovaquone is not mediated through its cycloguanil metabolite.
In studies, proguanil alone had no effect on mitochondrial membrane
potential or electron transport, but significantly enhanced the ability
of atovaquone to collapse mitochondrial membrane potential when
used in combination. This might explain why proguanil displays syn-
ergistic activity with atovaquone even in the presence of documented
proguanil resistance, or in patient populations who are deficient in
cytochrome P450 enzymes required for the conversion of proguanil to
cycloguanil.113
Atovaquone is a highly lipophilic compound with poor bioavailability.
Taking atovaquone with dietary fat increases its absorption, and therefore
tablets should be taken with a meal or a milky beverage. Atovaquone
is >99% protein bound and is eliminated almost exclusively by biliary
excretion. More than 94% can be recovered unchanged in the feces
over 21 days and <0.6% in the urine. The elimination half-life is about
2–3 days in adults and 1–2 days in children.114,115 Pharmacokinetic studies
in elderly patients and those with renal and hepatic impairment indicate
that no dosage adjustment is required for the elderly, or those with
moderate hepatic or mild to moderate renal impairment. However,
those with severe renal insufficiency (creatinine clearance <30 mL/min)
should not use atovaquone/proguanil because of potential elevated
cycloguanil levels and decreased atovaquone levels.
Efficacy and Drug Resistance.  AP is effective against malaria isolates
resistant to a variety of other antimalarial drugs. Resistance to atovaquone
develops rapidly if this drug is used alone.116 Resistance to the combina-
tion of atovaquone plus proguanil, although uncommon, has been
documented in a small number of cases following treatment courses
of AP (~25 reported cases).117–123 Most documented failures have occurred
in patients whose malaria was acquired in Africa. In the majority of
these cases, the malaria isolates had genetically confirmed markers of
resistance, notably mutations in the cytochrome b gene at position 268.
Treatment failure not associated with cytochrome b mutations has also
been reported in a small number of patients with low plasma drug
levels, and rarely in the presence of adequate drug levels.124 There are
rare published reports of documented failure associated with cytochrome
b mutations in persons using AP as a chemoprophylactic agent and
then only at low drug levels. Resistance in P. falciparum is associated
with mutation in the pfcytb gene. A study from India found that a
recrudescent P. falciparum isolate has a single mutation at position 268
(Tyr268Cys).125 This mutation has been previously described in a series
of cases with relapses of P. falciparum malaria after treatment with
atovaquone/proguanil.126 This suggests that if AP were to be widely
available in malaria-endemic areas, resistance would rapidly develop.
Breakthrough has been reported for P. malariae in the absence of
mutations in the pmcytb gene.127 This is likely due to a longer maturation
period of the P. malariae liver schizonts which are probably not susceptible
to atovaquone/proguanil.
156 SECTION 4 Malaria
In randomized controlled trials, daily atovaquone/proguanil at
recommended dosing was highly efficacious in preventing P. falciparum
malaria in both adults and children. Four published trials have examined
the protective efficacy of AP in 534 semiimmune adults and children
living in malaria-endemic areas.128–131 The overall efficacy of AP in the
prevention of P. falciparum malaria in these trials was 98% (95% CI
91.9%–99.9%). The most common reported adverse events attributed to
the study drug were headache, abdominal pain, dyspepsia, and diarrhea.
However, of note, all adverse events occurred with similar frequency
in subjects treated with placebo or AP, and there were no serious
adverse events.
The protective efficacy of AP for prevention of P. falciparum
malaria in nonimmune adults and children has been examined in
five clinical trials, four of which were randomized and three blinded.
Collectively, the protective efficacy of AP (evaluable in 1361 nonim-
mune individuals, of whom 126 were children under the age of 12)
was 96%–100% (95% CI 48%–100%). However, the determination
of protective efficacy in these trials was limited by their small sample
size, lack of a placebo control, and, as evidenced by the wide CI, these
studies were inadequately powered for the determination of protective
efficacy.
In two of the larger randomized, double-blind clinical trials, <2000
nonimmune subjects traveling to a malaria-endemic area received either
AP, daily for 1–2 days before travel until 7 days after travel, mefloquine
or chloroquine/proguanil, from 1–3 weeks before travel until 4 weeks
after travel.43,62
All drugs were well tolerated, but AP was significantly better tolerated
than either mefloquine or CP in these studies. Drug-related discontinu-
ation rates for AP versus mefloquine were 1.2% versus 5% (P = 0.001)
and for AP versus chloroquine/proguanil were 0.2% versus 2% (P =
0.015). In a comparative trial of AP versus doxycycline in 175 Australian
military participants, there were no prophylactic failures in either arm,
but AP was better tolerated, with a significantly lower rate of GI (29%
versus 53%) adverse events.
Only one randomized, double-blind, placebo-controlled trial has
evaluated the protective efficacy of AP against P. vivax. The protective
efficacy of AP was 84% (95% CI 45%–95%) for P. vivax and 96% (95%
CI 71%–99%) for P. falciparum.130 As AP does not appear to eradicate
P. vivax hypnozoites it is suggested that travelers to areas where the
transmission rates of P. vivax are high should be considered for presump-
tive antirelapse therapy with primaquine.
Taken together, these studies indicate that AP is an efficacious
chemoprophylactic regimen for P. falciparum. Additional data are required
to establish the efficacy against nonfalciparum malaria.
Tolerability.  Collectively the controlled trials indicate that AP at
prophylactic doses is well tolerated by both adults and children, with
drug discontinuation rates of 0%–2%. The most commonly reported
adverse events are gastrointestinal, which can often be reduced by taking
AP with food. According to the product monograph, when used for
malaria prevention the most commonly reported adverse events possibly
attributed to AP were headache and abdominal pain; however, in
placebo-controlled trials these occurred at similar rates in placebo
recipients. In the nonimmune traveler studies described earlier, par-
ticipants receiving AP reported significantly lower rates of neuropsy-
chiatric adverse events (14% versus 29%) and lower drug discontinuation
rates (1.2% versus 5%) than with mefloquine.59 Compared with CP,
AP users reported significantly fewer GI adverse events (12% versus
20%) and lower discontinuation rates (0.2% versus 2%). In a randomized
trial in travelers AP was the best-tolerated chemoprophylactic, with
discontinuation rates of 1.8% versus 3.9% for mefloquine and doxycycline
and 5.2% for chloroquine/proguanil.23
Efficacy and tolerability have also been examined in a randomized
comparative trial of AP versus CP in pediatric travelers.131 There were
no prophylactic failures, but AP was better tolerated, with no premature
discontinuation of AP due to an adverse event compared to 2% of
pediatric travelers using CP.
AP treatment and prophylaxis has (rarely) been associated with
severe dermatologic adverse events, including erythema multiforme
and Stevens-Johnson syndrome.132,133 Overall, systematic reviews of the
abovementioned randomized trials have concluded that AP is a well-
tolerated and highly efficacious chemoprophylactic agent for the preven-
tion of P. falciparum malaria.134
Contraindications, Precautions, and Drug Interactions.  AP is
contraindicated in those with severe renal impairment (creatinine
clearance <30 mL/min) and those with a history of hypersensitivity to
any of the drug components. AP should not be used to treat an individual
who has failed AP chemoprophylaxis, or anyone with evidence of severe
or complicated malaria.
The CDC approves AP for chemoprophylaxis in children weighing
>5 kg. Other guidelines specify that this chemoprophylaxis is only for
children weighing >11 kg.
AP is classified as a pregnancy category C drug. Based primarily on
lack of data, atovaquone/proguanil is not currently recommended for
the prevention of malaria during pregnancy or breastfeeding. However,
proguanil is considered safe during pregnancy, and animal studies
have revealed no teratogenicity for atovaquone. Three small studies
examining AP as treatment in pregnancy suggest that AP is safe and
well tolerated, but additional data are needed.135 A registry-based cohort
study of 570,877 births in Denmark examined whether exposure to
AP during the period of maximal susceptibility to teratogenic agents
(weeks 3–8) was associated with an increased risk of major birth defects.
Although there was a limited number of exposed women, there was
no observed increased risk associated with AP exposure during early
pregnancy.136
AP should not be given with other proguanil-containing medications.
Concomitant use with tetracycline has been associated with a 40%
decrease in plasma concentrations of atovaquone. Simultaneous use of
tetracyclines decreases plasma concentrations of atovaquone; and
rifampicin, rifabutin, and metoclopramide also reduce the concentration
of atovaquone and should be avoided. Atovaquone lowers the steady-state
concentration of azithromycin and increases the plasma concentration
of all protease inhibitors used for human immunodeficiency virus (HIV)
treatment,137 but the clinical significance is uncertain.
Indications and Administration.  AP is currently indicated for the
prophylaxis of P. falciparum malaria, including areas where chloroquine
and/or mefloquine resistance has been reported. Travelers who have
experienced intense exposure to P. vivax and P. ovale should be considered
for radical treatment with primaquine upon leaving the malaria-endemic
area. Because of its causal activity, AP is taken 1 day prior to travel in
a malarial zone, daily while exposed, and for 7 days upon leaving. It is
imperative that AP is taken with food, preferably a fatty meal to ensure
absorption of atovaquone which has very poor aqueous solubility. A
recent report describes failure of AP chemoprophylaxis and subthera-
peutic concentrations of atovaquone and proguanil in a traveler to
Ghana despite adherent dosing albeit on an empty stomach.138 Recent
publications suggest that shorter posttravel AP courses or a biweekly
prophylaxis may be future possibilities but more data are needed before
dosage changes can be sanctioned.139,140
Several European countries initially imposed limited duration
of use restrictions on AP use. A randomized double-blind study in
Papua demonstrated efficacy and tolerability over a 5-month period,
 CHAPTER 15  Malaria Chemoprophylaxis
and a 6-month open-label study reported good tolerability.141,142
Most countries now impose no time limits on the use of AP as a
prophylactic agent.
Primaquine
Introduction and Description.  Primaquine is an 8-aminoquinoline
that has been used for over 50 years for the terminal prophylaxis or
radical cure of relapsing forms of malaria (P. vivax and P. ovale),
owing to its ability to eradicate liver hypnozoite stages. Primaquine
was rediscovered as a malaria chemoprophylactic agent in the 1990s,
based on its ability to eliminate developing liver stages of P. falciparum
and P. vivax (causal prophylaxis).143,144 Primaquine has also gameto-
cidal activity against and has been used to reduce the transmission
of P. falciparum in malaria-endemic areas (see Fig. 15.1).145 A recent
meta-analysis and systematic review146 concluded that for persons
without G6PD deficiency, who are not pregnant, primaquine is the
most effective presently available prophylactic for P. vivax malaria and
comparable to such regimens as doxycycline, mefloquine, and atovaquone-
proguanil for the prevention of P. falciparum malaria. A revival of
primaquine as a priority malaria chemoprophylaxis may be on the
horizon.147,148
Pharmacology and Mode of Action
The precise mechanisms of action of 8-aminoquinoline drugs are
unknown. Primaquine localizes within the plasmodial mitochondria,
suggesting drug-induced mitochondrial dysfunction as one potential
mechanism of action. It is rapidly absorbed from the GI tract and
rapidly excreted. Peak plasma levels occur within 2–3 hours and the
mean half-life is approximately 4–5 hours. Primaquine is metabolized
to a carboxylic acid derivative of unknown antimalarial activity that
has a half-life of 24–30 hours.149
Efficacy and Drug Resistance.  In 2017 Kolifarhood et al. reviewed
the efficacy of primaquine versus P. falciparum and P. vivax malaria
and found an overall 74% reduction in the incidence of parasitaemia
by primaquine versus other prophylactic regimens146 was estimated
(relative risk [RR] overall = 0.26, CI 95% 0.16%–0.41%; RR vivax
= 0.16, CI 95% 0.07%–0.36%; RR falciparum = 0.31, CI 95%
0.18%–0.55%). There have been several randomized controlled field
trials: two in Indonesia, two in Colombia, and one in Africa that have
convincingly demonstrated the prophylactic potential of primaquine.
In four studies, adults with little previous experience of malaria were
given 30-mg base of daily primaquine for 12–52 weeks. Nonimmune
immigrants to Papua are intensively exposed to both P. falciparum
and P. vivax malaria. In 1995, a randomized placebo-controlled trial
indicated that daily primaquine for up to 1 year had a protective
efficacy of 95% (95% CI 57%–99%) against P. falciparum malaria and
90% (95% CI 58%–98%) against P. vivax malaria.150 A subsequent
trial in the same region in 1999–2000 over 20 weeks showed a protec-
tive efficacy of 88% (48%–97%) for P. falciparum and >92% (95%
CI >37%–99%) for P. vivax.151 In placebo-controlled field studies
in Colombian soldiers, primaquine was 94% efficacious (95% CI
78%–99%) against P. falciparum and 85% (95% CI 57%–95%) against
P. vivax.152 In an attempt to improve the efficacy rate against P. vivax
malaria, weekly chloroquine was added to the daily primaquine in a
subsequent field trial; however, the results were similar to those of
primaquine alone.153
Relapses of P. vivax malaria following standard courses of primaquine
(15-mg base/day for 14 days) are commonly reported from Papua New
Guinea, Papua, Thailand, and other parts of Southeast Asia and Oceania
(failure rates <35%), and less commonly from India and Colombia.
Smoak et al.154 reported high relapse rates in American soldiers deployed
157
to Somalia. Of 60 P. vivax–infected soldiers treated with standard doses
of chloroquine and primaquine (15-mg base/day for 14 days), 26 relapsed,
a failure rate of 43%. Eight soldiers had a second relapse following
another course of chloroquine plus primaquine therapy, including several
who completed a higher-dose primaquine regimen (30-mg base/day
for 14 days). Recently, failure of primaquine radical cure was shown in
persons with decreased activity of hepatitis enzyme cytochrome P450
(CYP) 2D6.155 This finding has shed light on the potential failure of
primaquine radical cure due to this enzyme deficiency. It has also raised
concern about using primaquine as primary chemoprophylaxis against
P. vivax.156
Tolerability.  Randomized controlled trials have shown that daily
primaquine is well tolerated, with reported discontinuation rates generally
≤2%. Kolifarhood et al.146 found that the incidence rate ratios for adverse
events showed no statistically significant difference between primaquine
and control groups. The most commonly identified adverse event has
been minor GI disturbances, which are minimized by taking the drug
with food. In a study by Baird and colleagues primaquine was as well
tolerated as placebo.151
Contraindications and Precautions.  The adverse events of great-
est concern with primaquine are methemoglobinemia and hemolysis
in G6PD-deficient persons. Primaquine-induced hemolysis can be
life threatening in a severely deficient person. Methemoglobinemia
is generally not a serious concern when <20% hemoglobin is in
the methemoglobin form; only rarely will testing for methemoglo-
binemia be indicated on clinical grounds, such as with cyanosis,
dizziness, or dyspnea. Controlled trials have demonstrated that
methemoglobinemia levels after 20 or 52 weeks of 30-mg base of
primaquine daily were no higher than those following standard 15-mg
base daily for 14 days.141,146 Methemoglobin levels have remained
<8.5% in recent trials, well below the 20%–30% associated with
symptoms.
Primaquine is contraindicated in G6PD deficiency and during
pregnancy because of the risk of hemolysis in the fetus. There is limited
experience with the prophylactic use of primaquine in children. Prior
to receiving primaquine individuals should be confirmed to have a
normal G6PD status by laboratory testing.
Primaquine should also not be used in individuals with NADH
methemoglobin reductase deficiency or those receiving potentially
hemolytic drugs.
Indications and Administration.  Randomized controlled trials in
Indonesia, South America, and Africa have demonstrated that primaquine
is an efficacious and well-tolerated chemoprophylactic agent (0.5-mg/
kg base per day; adult dose 30-mg base/day) against P. vivax and
P. falciparum. Because of its causal activity, it may be discontinued 1
week after leaving an endemic area. In many countries, primaquine is
not licensed for the chemoprophylaxis indication and it may not be
effective in persons who are intermediate metabolizers of CYP 2D6.
Until testing for CYP 2D6 genotype is available, the use of primaquine
as a chemoprophylactic agent requires caution.155,156
Current pivotal trials may be sufficient to meet regulatory require-
ments for this indication.
For individuals not taking primaquine as a chemoprophylactic agent,
and in whom exposure to P. vivax or P. ovale malaria is thought to have
been particularly high (e.g., long-term expatriates, soldiers), consideration
may be given to the use of primaquine to eliminate latent hepatic parasites
by administering a 2-week course (0.5-mg/kg base per day; adult dose
30-mg base/day) after return to a nonendemic area in individuals known
to be G6PD normal.145
158 SECTION 4 Malaria
FUTURE DIRECTIONS
Tafenoquine
Introduction and Description.  Tafenoquine is a primaquine analog
with a long elimination half-life (14–28 days versus 4–6 hours for
primaquine). It has activity against liver, blood, and transmission
stages of malaria. The long half-life of tafenoquine allows infrequent
dosing regimens. When the drug is taken with food, absorption
is increased by approximately 50% and the severity of GI adverse
events is diminished.155 In vitro and in vivo animal studies indicate
that tafenoquine is more potent and less toxic than primaquine
(see Fig. 15.1).156,157
Efficacy and Drug Resistance.  To date, trials have assessed the
prophylactic efficacy of tafenoquine in malaria-endemic areas.156–162 A
randomized dose-ranging study of tafenoquine was performed in Gabon
in older children and young adults. A loading dose strategy using 25-mg
base to 200-mg base of tafenoquine once daily for 3 days was evaluated.
Doses of 50 mg, 100 mg, and 200 mg daily for 3 days all showed
substantial protective efficacy through 10 weeks of follow-up. Compared
to placebo, tafenoquine 200-mg base daily for 3 days provided 100%
protection out to week 11.159
In a randomized placebo-controlled trial in semiimmune adults
in western Kenya, 200-mg base daily for 3 days followed by 200 mg
weekly for 13 weeks resulted in a protective efficacy of 87% (95% CI
73%–93%); 400 mg daily for 3 days followed by 400 mg weekly had a
protective efficacy of 89% (95% CI 77%–95%). One group received only
400 mg for 3 days at the beginning of the study followed by placebo.
The protective efficacy at week 15 in this group was 68% (95% CI
53%–79%); however, there were equivalent malaria rates to the weekly
treated groups out to study week 7, again supporting a fire-and-forget
dosing strategy.157
A randomized trial examined tafenoquine’s prophylactic efficacy
against P. falciparum in semiimmune adults in Ghana.158 Volunteers
received a loading dose of study drug on each of three consecutive days,
then a single weekly dose for 12 weeks. Doses of tafenoquine 200-mg
base afforded a protective efficacy of approximately 86%, similar to
protection afforded by 250 mg mefloquine weekly.
The prophylactic efficacy against P. vivax was evaluated in a placebo-
controlled trial in 205 nonimmune soldiers in the northeastern border
regions of Thailand. Using 400-mg base of tafenoquine daily for 3
consecutive days followed by a single monthly dose of 400 mg resulted
in a 95% protective efficacy against P. vivax.161 More recently, monthly
doses of tafenoquine (400 mg) were assessed in a randomized double-
blind placebo-controlled field trial in 205 Thai soldiers. Protective efficacy
against P. vivax was 96% (95% CI 76%–99%) and against P. falciparum
was 100% (95% CI 60%–100%).162 Nasveld and colleagues reported
the first phase 3 trial of the safety, tolerability, and effectiveness of
tafenoquine for malaria prophylaxis. Soldiers received weekly malaria
prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg meflo-
quine (162 subjects) for a 6-month deployment to Indonesia. No cases
of malaria were reported in either group during deployment. Three
participants on tafenoquine (0.6%) and none on mefloquine discontinued
prophylaxis because of possible drug-related adverse events. Mild vortex
keratopathy was detected in 93% of tafenoquine users but none of the
mefloquine subjects. The vortex keratopathy was not associated with
changes in visual acuity and was fully resolved by 1 year.163
Tolerability.  A recent pooled analysis of safety data found that weekly
administration of tafenoquine for up to 6 months increased the incidence
of GI AE, certain infections, and back/neck pain, but not the overall
incidence of AE versus placebo.164 Adverse events that occurred at an
incidence ≥1% in tafenoquine users and also at a higher incidence than
in the placebo group were diarrhea, nausea, vomiting, gastroenteritis,
nasopharyngitis, sinusitis, tonsillitis, laceration, ligament sprain, back
pain, neck pain, and rash. Among these, only gastroenteritis and back
pain occurred in >5% of subjects in both subgroups. In early studies,
the most commonly reported adverse event noted during tafenoquine
prevention trials has been mild GI upset. Other adverse events have
included dermatologic problems, headaches, and mild transient elevations
in serum liver transaminases. Initial clinical trials also suggested that
longer-term use of tafenoquine might be associated with corneal deposits
and increases in serum creatinine. A recent randomized trial of 120
volunteers taking 200 mg of tafenoquine for 6 months showed no
clinically significant effects of tafenoquine on ophthalmic or renal
function.165
Contraindications, Precautions, and Drug Interactions. The
potential toxicities of concern with tafenoquine are the same as for
primaquine: methemoglobinemia or hemolysis in G6PD-deficient
persons. During the Kenyan field trial, two G6PD-deficient individuals
were inadvertently given tafenoquine, which resulted in significant
intravascular hemolysis requiring blood transfusion in one case.
Indications and Administration.  The anticipated clinical chemo-
prophylactic dose of tafenoquine will be 200 mg/day for 3 days (total
of 10 mg/kg over 3 days in a 60-kg person) followed by 200-mg
maintenance doses thereafter (3.3 mg/kg weekly in a 60-kg person).146
High priority will be a point-of-care test to assess for G6DP
deficiency.
NEW PIPELINE DRUGS FOR MALARIA
CHEMOPROPHYLAXIS
There has been recent robust activity in discovery and testing of new
antimalarial drugs.166 Automation, new technologies, and new collabora-
tions have made it possible to do phenotypic screening at a relatively
low price on large numbers of compounds. The use of a human
experimentally induced infection model has made it possible to study
the effect of new agents in human volunteers with a low level of infection.
The human-induced malaria model has now been used in a number
of trials and allows the more rapid generation of key performance
characteristics of antimalarials at different times and dosages. In this
model, healthy nonimmune volunteers are inoculated with sporozoites
or with infected erythrocytes. The dose can be controlled, and PCR-based
parasite detection methods allow monitoring and treatment at a pre-
defined threshold (before the onset of symptoms).
Phase 1 studies have been published showing that DSM265, a novel
antimalarial that inhibits parasite dihydroorotate dehydrogenase, which
is essential for pyrimidine biosynthesis, appears to be well tolerated. It
cleared P. falciparum parasites in a human challenge model though
clearance was slower than with mefloquine, the comparator drug.167,168
It has a long half-life and activity against the blood stage and liver stage
schizont, so this novel drug could potentially be useful as a prophylactic
agent. It apparently lacks activity against hypnozoites, thus would not
be useful for radical cure of P. vivax infections.167 Because of the risk
of development of resistance, it is likely to be combined with another
more rapidly acting agent.
Another novel entity is designated KAF156. This is an imidazole
piperazine with activity against asexual and sexual blood stages of P.
falciparum (including artemisinin-resistant parasites) and P. vivax. It
is also active against the preerythrocytic liver stages. It is currently
undergoing trials to assess its potential to treat and prevent infection
and to block transmission.169,170
 CHAPTER 15  Malaria Chemoprophylaxis
CHEMOPROPHYLAXIS IN SPECIAL POPULATIONS
Pregnant and Breastfeeding Travelers
Falciparum malaria in a pregnant woman poses significant risks for
the mother, fetus, and neonate. A pooled analysis of data on imported
malaria in pregnant women showed that malaria (P. falciparum and P.
vivax) is associated with an increased risk of spontaneous abortion and
stillbirth, intrauterine growth retardation, premature delivery, and
maternal mortality.171 Travel by pregnant women, or women who might
become pregnant, to malaria-endemic destinations should be avoided
or deferred when possible. This advice is based on the fact that most
effective antimalarial regimens are neither recommended nor adequately
studied during pregnancy, especially in the first trimester.
If a pregnant woman must travel to an area with CRPf malaria, the
use of insect repellents and insecticide-treated bednets should be strongly
encouraged and chemoprophylaxis should be used.
An evaluation of the use of mefloquine chemoprophylaxis by nonim-
mune pregnant women suggests that it is reasonable to recommend
mefloquine prophylaxis in all trimesters when travel cannot be deferred
and when the woman is at a high risk of malaria.80 This analysis, which
detailed outcomes of pregnant women who were exposed to mefloquine
in the preconception period and in pregnancy, showed that the birth
defect prevalence and fetal loss in maternal, prospectively monitored
cases were comparable to background rates.80 These data further confirm
that inadvertent conception while on mefloquine is not an indication
for termination of pregnancy.
At present there are insufficient data on the use of atovaquone/
proguanil in pregnancy or breastfeeding, and therefore it is not recom-
mended unless the potential benefit outweighs the risk. However, data
are available on the use of atovaquone or proguanil alone and it appears
that the use of these agents singly do not cause harm in pregnancy.
Doxycycline is contraindicated in pregnancy and breastfeeding.
Conception should be delayed until 1 week after completion of doxy-
cycline. Doxycycline crosses the placenta and therefore may cause
permanent discoloration of teeth, damage to tooth enamel, and impair-
ment of skeletal growth in the fetus. Some experts (United Kingdom
and Swedish) allow the use of doxycycline prophylaxis in early pregnancy
(first trimester).
Chloroquine alone or in combination with proguanil is safe in
pregnancy and lactation; however, these agents only offer partial protec-
tion in areas with transmission of CRPf. Some sources recommend
supplementation with folic acid for pregnant women taking proguanil.
Breastfeeding.  Doxycycline is excreted in breast milk and therefore
may cause discoloration of teeth, damage to tooth enamel, impairment
of skeletal growth, and photosensitivity in breastfed infants depending
on their stage of development.
Primaquine is contraindicated in pregnancy, although it is considered
safe in breastfeeding provided that the infant and mother are both
screened for G6PD deficiency. In practice primaquine is not recom-
mended for pregnant or breastfeeding women.
Long-Term Travelers
Few data are available on efficacy and tolerability of long-term malaria
chemoprophylaxis. Adherence issues are challenging, and the long-term
traveler requires expert advice on malaria risk at the destination, pos-
sible seasonality, and practical guidance regarding long-term use of
medications.5,172 Mefloquine has been used successfully for periods up
to 2.5 years by Peace Corps volunteers in Africa5,72 and was shown
to be well tolerated and effective in preventing falciparum malaria. A
pharmacokinetic study has shown that toxic accumulation does not
occur during long-term intake.173 Atovaquone/proguanil can be used long
term,174 although some countries restrict the use of AP to short-term
159
travel up to 28 days. In the United States and Canada there is no limit
on the period of prophylaxis. There are few data on the long-term use of
doxycycline malaria chemoprophylaxis for periods >6 months, but long
courses of doxycycline have demonstrated good safety and tolerability
when used to treat conditions such as acne, rosacea, brucellosis, and
Q fever.
Despite the strong recommendations for malaria chemoprophylaxis
for Peace Corps volunteers serving in Africa and the availability of three
chemoprophylaxis options, a survey in 2013 found an overall adherence
of 73%: 88% for atovaquone-proguanil, 83% for doxycycline, and only
62% for mefloquine.172 The investigators found that the most common
reasons for nonadherence were forgetting to take prophylaxis (90%),
fear of long-term adverse events (54%), and having experienced adverse
events attributed to prophylaxis (51%).172 Malaria risk among volunteers
had reached 18 cases per 100 volunteer-years during 2009–2012; therefore
the survey illustrated a continued need to improve adherence to che-
moprophylaxis in this group of long-term travelers. A recent study of
illness during long-term follow-up of volunteers to the Peace Corps
who used chemoprophylaxis found no significant difference in illness
between users and nonusers of malaria chemoprophylaxis including
psychiatric illness in screened mefloquine users. These results should
reassure prophylaxis users and increase adherence.72
In addition to challenges in adhering to chemoprophylaxis, long-term
travelers also need to persist in their practice of personal protection
and safer behaviors. For instance, insect protection measures such as
insecticide-treated bednets, which has demonstrated effectiveness in
preventing malaria, and insect repellents that effectively reduce mosquito
bites are essential components of malaria protection for long-term
travelers.
Regarding chemoprophylaxis in long-term travelers, key points to
discuss in assessment and recommendation include:
• Details of itinerary, accommodations, activities, modes of transporta-
tion, potential for deviation from plans
• The traveler’s underlying health as well as beliefs, preferences,
behaviors, and likelihood in adhering to medication
• The traveler’s understanding of malaria
• The traveler’s budget constraints
• Availability and accessibility of reliable medical care during travel
• Advice obtained elsewhere by the traveler (Internet, family, friends,
and contacts at destination)
• The possibility of falling ill with symptoms suggesting malaria while
in remote location, and needing a course of malaria treatment
on hand
In sum, the approach for long-term travelers should provide reason-
able options for chemoprophylaxis, detailed understanding about how
to prevent malaria transmission, strategy for emergency self-treatment,
and plans to access reliable medical care.
Business Travelers
Business travelers are a diverse population of travelers with varying
work activities when they travel, ranging from meetings in urban settings
to field work in remote and austere locations. Several studies have
identified business travelers to be a major risk group for acquiring
malaria from developed countries as well as emerging economies.6,175,176
The GeoSentinel Surveillance Network, which currently consists of 64
travel and tropical medicine clinics in 29 countries, found that expatriates
returning from Africa had higher proportionate morbidity for malaria
than nonexpatriate travelers.6 In the United States, business was the
purpose of travel in 19.2% of fatal malaria cases. An analysis of malaria
cases in UK residents in 2007 reported significantly higher hazard of
acquiring malaria by business travelers and travelers visiting friends
and relatives compared to holiday makers.177 In China, a large proportion
160 SECTION 4 Malaria
FIG. 15.4  Malaria risk zones. Reproduced with permission of Dr. Bernhard R. Beck and Dr. Olivia Veit.
of imported malaria cases have occurred in recent years among overseas
workers; most have had exposure in Africa where business relationships
have increasingly developed between China and Africa.175,176
Berg et al.178 conducted a web-based survey in 2005 among frequent
business travelers of Shell International and found that all survey
participants recognized fever as a malaria symptom, but knowledge of
incubation period was poor. Nearly all reported adhering to appropriate
personal protective measures. Most of the business travelers going to
high-risk areas for malaria identified them accurately to be at risk and
92% carried malaria chemoprophylaxis. Among those who went to
areas with malaria risk but did not carry chemoprophylaxis, half had
received company occupational health advice; some reported that they
were advised not to take chemoprophylaxis and some decided on their
own that it was not needed (Fig. 15.4). A similar survey of a commercial
airline crew from the United States found that the majority of respondents
were able to correctly identify effective malaria prevention measures:
malaria chemoprophylaxis medication and insect repellents (91%–96%).179
Yet their behavior contradicted the knowledge. Adherence to chemo-
prophylaxis was poor; while the majority of the crew spent >30 minutes
outdoors after sundown and did not use repellents, only 4% of the
flight attendants and 40% of the pilots adhered completely.179
Most recently, an analysis of GeoSentinel data on >12,000 ill business
travelers seen after travel in 1997–2014 found that 9% of the diagnoses
were malaria, one of the most frequent specific diagnoses overall.180
The vast majority of the >1000 patients with malaria took no chemo-
prophylaxis or did not adhere to their chemoprophylaxis; nearly all of
the patients with severe malaria were due to P. falciparum and nearly
all had exposure in sub-Saharan Africa. Finally, over half of the 13
deaths recorded were due to malaria.180 Clearly, malaria prevention in
business travelers needs improvement. Countries and companies vary
in their current requirements and needs for business travelers. The
degree of malaria exposure for business travelers ranges widely depending
on destination, type of work, activity, and accommodations and are
influenced by individual risk perception and practices.
Migrant and VFR Travelers
The displacement of populations due to natural disasters or political/
economic instability in recent decades has led to migration from
malaria-endemic countries to nonendemic countries. In time, the
migrants return to their countries of origin to VFR, with associated
risk of malaria.1,181–183 An analysis of imported malaria in Barcelona,
for example, found that 41% were VFR and 14% were recently arrived
immigrants.184 Among 7629 migrants from 153 countries seen in
GeoSentinel clinics in 19 countries from 1997 to 2009, malaria was one
of the most common diagnoses, along with latent tuberculosis, viral
hepatitis, active tuberculosis, HIV/AIDS, schistosomiasis, and strongy-
loidiasis.181 Malaria was especially common with febrile patients and
hospitalized patients. Among the patients who were hospitalized, 21%
had febrile illness and 83% were attributed to malaria.181
It has been repeatedly illustrated that malaria affects VFR travelers
disproportionately.1 In 2013, 1727 cases of malaria were reported to
the US CDC, among which 70% with known purpose of travel was
 CHAPTER 15  Malaria Chemoprophylaxis
visiting friends and relatives.183 Of nine reported fatalities that described
a purpose for travel, six were VFR, illustrating the high malaria risk
and severe disease associated with this group of travelers.183 The dis-
proportionate impact of malaria on VFR travelers is further evident
from cases of malaria in pregnant women.171 Collaborators from Europe,
the United States, and Japan pooled data and described 631 cases of
pregnant women with malaria, where they found VFR was the main
reason for travel (58%), and most cases were P. falciparum acquired in
West Africa.171
Nevertheless, malaria species distribution may be influenced by the
origin countries of migrants. Because migration patterns shift over
time, there may be an accompanied shift in species identified. During
the ongoing waves of migration from Africa to Europe since 2013, the
Netherlands has seen a sharp increase in imported malaria in asylum
seekers as well as VFR travelers.182 In 2014–2015, most malaria cases in
VFR travelers in the Netherlands were due to P. falciparum that were
exposed in Central and West Africa, while most asylum seekers with
malaria were infected with P. vivax in the Horn of Africa.182 In the
future, these asylum seekers may return to the Horn of Africa as VFR
travelers and may lead to an increased proportion of vivax malaria
diagnosed in the Netherlands.
Additionally, a gradient of risk has been proposed within the VFR
traveler population, including that for malaria.2 This may have resulted
from the familiarity of a migrant with certain disease risks in the country
of origin and the assumption that he or she has partial immunity from
having lived in the endemic country. Therefore a “migrant VFR” may
behave differently and experience divergent levels of risk compared to
a “traveler VFR.” More specifically, malaria was more commonly
diagnosed among “immigrant VFRs” than “traveler VFRs.”
Given their increased risk for malaria, VFR travelers should ideally
receive pretravel health advice, but multiple studies have found VFR
travelers to be underserved by pretravel consultations.1 Earlier studies
have shown that it is cost effective to subsidize chemoprophylaxis for
VFRs to West Africa and thus avoid the costs of the treatment of imported
malaria.185,186
When VFR travelers do receive pretravel advice, the bias toward
increased imported malaria is eliminated.1 A potentially fruitful approach
is to query patients during their routine primary care appointments
regarding their future travel plans. Such active screening for intended
travel activities can identify future VFR travelers, determine high-risk
itineraries, and lead to education regarding the importance of seeking
appropriate pretravel health preparation.4
Even if VFR travelers recognize their increased risk and seek pretravel
health advice, malaria chemoprophylaxis still faces other challenges:
cost of medication, adherence to chemoprophylaxis, and misdirection
to discontinue medication from family or friends residing in endemic
countries. Detailed discussions with VFR travelers regarding the many
facets of malaria prevention and chemoprophylaxis will require spending
extra time. But a clear understanding regarding malaria and the preventive
strategies will be well worth the effort to achieve reduction of malaria
in VFR travelers.
Infants/Children
Because of their less mature immune system and inexperience in
responding to symptoms of illness, young children are especially vulner-
able to malarial infection and can develop high parasitemia rapidly. In
pediatric travelers from the Boston area (≤18 years), VFR children were
much more likely to travel to malaria-endemic countries, and 35%
reported VFR as the purpose of travel.187 Nearly half of VFR children
were <5 years old, and about a third were ≤2 years, much higher than
non-VFR children. Not surprisingly, reports on imported malaria in
children have shown higher rates for those traveling to VFR, particularly
161
returning from Africa, relative to those traveling for other reasons.188
Despite large numbers of children traveling to malaria-endemic areas
and large numbers of imported malaria cases in children, there are very
few data on the use of antimalarials as chemoprophylaxis for children.
The use of mefloquine in children has been reviewed.189 A simulated
mefloquine plasma profile showed that doses to achieve protective
chemoprophylaxis blood concentration of mefloquine of approximately
620 ng/mL (or 1.67 µmol/L) in children should be at least 5 mg/kg.
This simulated plasma profile in children corresponds to that seen in
adult travelers using a weekly prophylaxis dose of 250 mg. This reinforces
current practice of using weight-based dosage for children. Mefloquine
clearance per body weight is higher in older children.189
Advise for families traveling with children to malaria-endemic areas
should emphasize the potentially rapid and progressive course and severe
complications. Families should obtain medical evaluation promptly for
any suspicious symptoms. Preventive strategies are the same as those
for adults. Repellents are generally considered safe in children aged >2
months (unless the product information states otherwise), except for
oil of lemon eucalyptus, which should only be used in children ≥3
years. Specific tips for families include:
• Adults should apply repellents on children rather than letting young
children apply.
• Avoid children’s hands in case they lick, and avoid eyes, mouth, and
around the ears.
• Upon returning indoors, cleanse off skin or bathe to remove repellent
to reduce accumulation.
DIFFERENCES IN GUIDELINES AND
RECOMMENDATIONS ON MALARIA
CHEMOPROPHYLAXIS
Many countries publish and regularly update recommendations for
malaria chemoprophylaxis (e.g., Canada, United Kingdom, Scotland,
France, Switzerland, Netherlands, United States, Australia) (see Table
15.5). Other organizations and groups share guidelines for the prevention
of malaria (e.g., WHO, International Association for Medical Assistance
to Travellers [IAMAT]). Most of these are freely available to health care
providers; some are also intended for travelers. Some are official guidelines
for a country; others aim for an international audience. They are updated
with variable frequency, and there is notable variation in the recom-
mendations. The recommendations may have financial implications if
they determine which drugs will be covered or legal ramifications based
on recommendations for specific patients or destinations.
It should be noted that in general, the greatest agreement in recom-
mendations exists for geographic areas with highest malaria risk (i.e.,
sub-Saharan Africa). It is worth observing that as malaria transmission
decreases and is close to elimination in many countries, the number
of countries or geographic regions with divergent recommendations is
likely to increase. Greatest divergence exists for countries with low or
moderate risk where chemoprophylaxis or standby emergency treatment
may be recommended. Guidelines generally agree that all travelers to
areas with malaria should use mosquito avoidance measures though
they may vary in the detail provided.
Three questions are relevant: How do guidelines differ? Why do
they differ? What are the consequences? The drugs that are recommended
differ. In most recommendations chloroquine, atovaquone-proguanil,
mefloquine, and doxycycline are among the options for chemoprophy-
laxis. Some also list hydroxychloroquine as an alternative to chloroquine
for areas with chloroquine-sensitive malaria. Several country guidelines
(e.g., United Kingdom, France, Hong Kong) continue to list proguanil
as a single agent or combined with chloroquine. In the United Kingdom,
chloroquine and/or proguanil and atovaquone/proguanil can be
162 SECTION 4 Malaria
purchased from local pharmacies without a prescription (in contrast
to other antimalarials available in the United Kingdom).
Primaquine.  Clear differences exist for primaquine, which is not
recommended for primary prophylaxis for any situation in most
guidelines. UK guidelines note that primaquine is not licensed in that
country; both the United States and Canada list primaquine as an option
for primary prophylaxis (as well as for presumptive antirelapse therapy
or terminal prophylaxis) for travelers to areas with only or primarily
P. vivax malaria. Its use for primary prophylaxis is considered off-label
in the United States, though it is listed as one of the recommended
options in the country. The CDC’s Health Information for International
Travel supports US providers who decide to recommend it. Those
guidelines specifically note that it is a good choice for travel to places
with >90% vivax malaria, shorter trips, and for last-minute travelers.
Canadian guidelines say that primaquine is not a first line chemopro-
phylactic agent but may be considered as an alternative when other
agents are contraindicated. All guidelines that mention primaquine
highlight the need to test for G6PD deficiency before considering its
use. Point-of-care G6PD testing will have increasing importance for
future primaquine and tafenoquine recommendations.190
Country recommendations may reflect local availability of drugs or
licensing. Ease of off-label use may vary; restrictions about use (e.g.,
mefloquine) may also differ. Recommendations about maximum duration
that a drug can be used may vary. Some countries are mandated to use
a specific checklist before prescribing mefloquine.58 Minor differences
exist about dosing, duration, age cutoffs, and specific risk groups
(infancy, pregnancy, breastfeeding, renal failure, hepatic dysfunction,
etc.) for several of the drugs and a recent study shows wide variation in
expert recommendations on malaria prophylaxis for the forementioned
niche groups.191
Moderate-to-low malaria risk is defined as one infection per 10,000
travelers192 but most guidelines do not define risk quantitatively. The
US guidelines specify “estimated relative risk for US traveler” and use
terms very low, low, moderate, and high. The UK guidelines use descriptors
that range from no risk, low to no, very low, low, moderate, to high. Some
recommendations use duration of travel as a threshold for recommending
prophylaxis. For example, for certain locations prophylaxis is not recom-
mended for travel <1–2 weeks’ duration.
Major differences exist in recommendations about the use of standby
emergency treatment (SBET), with some guidelines suggesting it be
used only in limited situations when access to local care is not available
and others recommending it be used for most areas with low to moderate
risk of malaria (see Chapter 16).
Many factors underlie the differences in recommendations: differences
in drugs that are licensed and available; perception of risk; willingness
to tolerate different kinds of risk (e.g., adverse event related to drug
versus acquisition of malaria); traveler’s preferences; traveler’s willingness
to use insect avoidance measures; traveler’s comfort with carrying standby
treatment; public opinion and media reports of adverse reactions; and
economics. Travelers from a given country often have family and cultural
ties with a specific geographic area that may influence common travel
destinations and knowledge of risk in a particular destination. Expert
groups must make recommendations in the absence of accurate, current,
and complete data.191 Guidelines often change slowly while the on-the-
ground events may evolve more rapidly. Epidemiology of malaria is
dynamic; parasites may become more resistant; knowledge of previously
unknown adverse events may become available; new drugs may be
licensed. Preparation of guidelines requires meetings, consensus, and
review; even when the guidelines change, health care providers may be
slow to accept and follow new recommendations.
What are the consequences of variable recommendations? The wide
divergence can undermine confidence in them. Some guidelines are simply
out of date, so health providers will want to access the most current
ones—ideally those that are accessible online and regularly updated.
One advantage of having guidelines that are thoughtfully developed
but different is that they can provide clinicians with a second opinion
or an alternative approach. At the same time, it would be useful to
have a shared framework for describing risk and common metrics and
shared definitions to provide better communication. Thresholds for
interventions could still vary but communication would be simpler across
countries and populations. Shared data about malaria in travelers and
in local populations will also allow more informed recommendations
and decisions. As malaria comes under control in many countries,
the role of travel/travelers in reintroducing malaria will need to be
considered.
National ideologies will continue to shape malaria prevention recom-
mendations. While harmonization of recommendations can be a
long-term goal, current guidelines must be responsive to change based
on drug data and malaria epidemiology and should be evidence based.
Malaria chemoprophylaxis is destined to remain a complex, controversial,
and challenging area of pretravel advice for many years to come.
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